Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue10.2000:
Low Growth Hormone Response to Growth Hormone–
Releasing Hormone in Child Depression
Ronald E. Dahl, Boris Birmaher, Douglas E. Williamson, Lorah Dorn, James Perel,
Joan Kaufman, David A. Brent, David A. Axelson, and Neal D. Ryan
Background: This study examined growth hormone (GH)
response to growth hormone–releasing hormone (GHRH)
in a large sample of depressed children compared with
normal control children. Within-subject comparisons were
also performed in control subjects to examine test–retest
reliability and in depressed children comparing episode
versus clinical recovery.
Methods: The sample included depressed children (n 5
82) and normal control children (n 5 55) group-matched
for age, gender, and pubertal status; the mean ages were
11.2 6 1.7 and 11.2 6 1.8 years, respectively. We gave
GHRH (0.1 mcg/Kg) at 9 AM, and serum GH levels were
determined every 15 min from 230 min through 190 min
of the GHRH infusion. A subgroup of normal control
subjects (n 5 11) repeated the protocol for test–retest
reliability within a 2-month interval. A subgroup of
depressed children (n 5 20) were restudied off all medications following full clinical remission from depression.
Results: The mean GH response to GHRH was significantly lower in the depressed group (8.7 ng/mL 6 SEM
0.9) compared with normal control children [12.2 ng/
mL 6 SEM 1.3; t(135) 5 2.59, p 5 .01 effect size 0.44].
The test–retest reliability of GH response to GHRH was
stable (intraclass correlation 5 .93 for mean post-GH).
The GH response to GHRH remained low in subjects
restudied during clinical remission from depression.
Conclusions: Depressed children show low GH response
to GHRH. The measure appears to be reliable, and the low
GH response continues following clinical remission. Further studies are needed to explore the mechanism and
relative specificity of this finding. Biol Psychiatry 2000;
48:981–988 © 2000 Society of Biological Psychiatry
Key Words: Depression, growth hormone, growth hormone–releasing hormone, development, children,
adolescents
From the Department of Psychiatry, University of Pittsburgh School of Medicine,
Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania (RED, BB,
DEW, LD, JP, DAB, DAA, NDR) and the Department of Psychiatry, Yale
University School of Medicine, New Haven, Connecticut (JK).
Address reprint requests to Ronald E. Dahl, M.D., University of Pittsburgh Medical
Center, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh PA 15213.
Received January 8, 2000; revised May 1, 2000; accepted May 18, 2000.
© 2000 Society of Biological Psychiatry
Introduction
P
rogress in understanding affective disorders over the
past decade increasingly has focused attention on
questions of maturational influences on biological systems
of interest. There has been considerable interest in 1) the
effects of early adverse experiences on later expression of
affective dysregulation, 2) the increasing rates of depression during adolescent development, 3) the emergence of
gender differences in rates of depression during adolescent
development, and 4) changes across childhood, adolescence, adulthood, and geriatrics in specific domains, such
as symptom profile, clinical course, genetic influences,
and treatment response. Broadly speaking, this work has
yielded some areas of maturational continuity, as well as
areas of developmental variation (Angold et al 1998;
Birmaher et al 1996a, 1996b; Garber et al 1993; Harrington et al 1994; Kovacs 1996; Puig-Antich et al 1993;
Rao et al 1995; Ryan et al 1987).
This theme of both similarities and differences across
child, adolescent, and adult depression also has been
evident in psychobiologic studies. For example, HPA-axis
alterations and electroencephalogram (EEG) sleep
changes associated with depression show considerable
maturational variance (Dahl 1996; Dahl et al 1991a,
1991b, 1992, 1994, 1996; Emslie et al 1994). In contrast,
low growth hormone (GH) response to pharmacologic
challenges seen in association with depression has shown
relative continuity across development, including depressed samples ranging from prepubertal children
through old age (Jarrett et al 1990, 1994; Lesch et al 1987,
1989; Meyer et al 1991; Puig-Antich et al 1984c, 1984d;
Ryan et al 1988, 1994; Siever et al 1992).
There is also preliminary evidence that this low GH
persists after clinical recovery (in a medication-free state)
in depressed children (Puig-Antich et al 1984d) and
following treatment for depression in adults (Jarrett et al
1994).
Recently, our research group has found that low GH
response to growth hormone–releasing hormone is also
evident in children and adolescents with no personal
history of depression but with high rates of affective
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BIOL PSYCHIATRY
2000;48:981–988
illness in their families (Birmaher et al 2000). These
results have been considered within an emerging model
based on the hypothesis that low GH response to GHRH
represents a stable trait marker for affective illness—a
marker evident before the onset of depression, persisting
across episode and recovery, and independent of age and
maturational changes.
The studies reported in this paper address the basic
foundation for further investigations of this model, focusing on three specific aims: 1) to extend earlier findings of
low GH response to GHRH by comparing a large sample
of depressed children and well-matched control subjects
with careful assessment of psychiatric and family history
data, 2) to examine the reliability of GH responses to
physiologic stimuli (within-subject test–retest reliability),
and 3) to examine GH responses after clinical recovery
within a subset of depressed children studied initially
during a depressive episode.
Methods and Materials
Phase 1 and Phase 2 Studies
The data described in this paper include GH data collected in two
similar studies. The research facility, most of the personnel, GH
assay procedures, and design of the study up to and including the
GHRH test were identical. Phase 1 of the study included a larger
number of neuroendocrine tests after the GHRH test; a later
phase of the study had a shorter neuroendocrine protocol. The
GHRH data from n 5 36 children with major depressive
disorder (MDD) n 5 18 normal control subjects from phase 1
studies were included in a preliminary report (Ryan et al 1994).
All of the phase 2 data are new, and there is no overlap with any
previously reported GH data. The methods for the GHRH test
measures and protocol were identical across studies, and analyses
were performed showing that there was no effect of phase on any
of the GH measures being examined, thus the data were combined across phase 1 and phase 2 studies to maximize the power
to examine covariates and subgroup effects.
Recruitment and Inclusion–Exclusion Criteria
Depressed children were recruited from the inpatient and outpatient clinics at Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center. Normal control children were
recruited through advertisement and personal contacts. Informed
consent to participate in the study was obtained in accordance
with the University of Pittsburgh Institutional Review Board
guidelines. Inclusion criteria common for all subjects were that
they be 7 to 15 years of age and medically healthy. Children in
the depressed cohort were required to meet DSM-III-R criteria
for MDD. Additional exclusion criteria for the MDD cohorts
only included 1) concurrent DSM-III-R diagnosis of anorexia
nervosa, bulimia nervosa, autism, schizoaffective disorder, or
schizophrenia and 2) MDD chronologically secondary to conduct
disorder.
For the normal control subjects only, additional inclusion
R.E. Dahl et al
criteria included 1) no lifetime history of any psychiatric disorder
and 2) low familial risk for affective illness. In this study, low
familial risk for affective disorder was operationally defined as
having no first-degree relative with a lifetime episode of any
affective disorder or schizophrenia spectrum illness; no seconddegree relative with a lifetime history of recurrent, bipolar, or
psychotic depression, schizoaffective disorder, or schizophrenia;
and no more than 20% of second-degree relatives with a single
episode of MDD.
Exclusion criteria for both groups were 1) significant medical
illnesses, 2) medications (except acetaminophen) within 2 weeks
of the study, 3) inordinate fear of needles, 4) obesity (weight
greater than 150% of ideal body weight) or severe growth failure
(weight or height less than 3% of the National Health Statistic
Curve), and 5) mental retardation or the presence of a specific
learning disability.
DIAGNOSTIC ASSIGNMENT. Diagnostic assessments of the
depressed cohorts were completed by research assistants who
administered the Present Episode (Chambers et al 1985) and
Epidemiologic (Orvaschel and Puig-Antich 1987) versions of the
semistructured diagnostic interview, the Schedule for Affective
Disorders and Schizophrenia for School-Aged Children (KSADS). The diagnosis of MDD was made using DSM-III-R
criteria, with the presence of all positive symptoms confirmed by
a child psychiatrist or psychologist. For normal control subjects,
if an initial telephone screen of the family indicated preliminary
eligibility and interest, the child’s lifetime history of psychiatric
symptomatology was assessed using only the K-SADS-E (Orvaschel and Puig-Antich 1987). All symptom ratings were made
by interviewing the parent(s) first, then interviewing the child.
All children who participated in the study were reinterviewed
using a short version of the K-SADS at the time of the
psychobiological studies to confirm presence of depressive
symptomatology.
All interviews were carried out by trained research clinicians
blind to the subject’s clinical status under the supervision of child
psychiatrists (DA, BB) or a child psychologist (JK). Interrater
reliability for all diagnoses for our studies has been k $ .70.
Socioeconomic status (SES) was measured using the Hollingshead four-factor index (Hollingshead 1975).
GHRH TEST. Following a visit and orientation to the laboratory, children and family members arrived in the lab to begin
the psychobiological study at 5 PM. The sleep–neuroendocrine
laboratory is furnished with many age-appropriate materials,
including books, art supplies, board games, entertainment videos,
and computer games. Children are given considerable individual
attention from staff with years of experience conducting biological studies with children. On a rating scale completed immediately after finishing the psychobiological studies, the majority of
children who participated in this and other studies conducted in
the lab rated the experience as “very positive” (Dahl and Ryan
1999).
An intravenous line was placed within the first hour of the
study, and children are then free to play interactive games, watch
movies, and so forth for the rest of the evening. Before bedtime,
EEG leads were placed for standard sleep recordings. On the
Growth Hormone in Child Depression
following morning, baseline blood samples for GH were obtained through the indwelling catheter at 8:30, 8:45, and 9:00 AM.
Immediately following the 9:00 AM draw, children received an
infusion of 1.0 mcg/kg of GHRH over 2 min. There were no
significant side effects of any sort related to the GHRH test.
Children generally showed no signs of behavioral reaction of any
kind. A physician was in attendance throughout the procedure.
Following GHRH administration, blood samples for GH were
obtained every 15 min for a total of 90 min. The child remained
fasting from bedtime (of the previous evening) until completion
of the GHRH test.
BLOOD SAMPLES AND GH ASSAYS. Blood samples were
collected in plastic tubes containing edetic acid (EDTA) then
centrifuged immediately in a refrigerated centrifuge. Plasma was
separated and stored at 280°C until assayed. Human growth
hormone levels were measured on a 50 mL plasma sample, run in
duplicate. A modified version of the double antibody 125I
radioimmunoassay procedure developed by Diagnostic Products
Corporation (Los Angeles) was used for these determinations. To
increase the sensitivity of the assay to 0.5 ng/mL of growth
hormone from that of the straight kit procedure, the amount of
antibody was decreased, and a longer, sequential incubation of
the antibody and radiolabeled antigen was used. Subjects’
duplicates with a coefficient of variation exceeding 5.0% were
retested. The range for the intraassay variation of subjects’
sample duplicates was 0.00 to 4.98% CV, with a mean of 0.87%
CV. Interassay variation ranged from 20.15% CV (mean of 2.47
ng/mL) to 13.68% CV (mean of 12.31 ng/mL).
Statistical Analyses
Sample characteristics were compared using analyses of variance, x2, and Fisher’s exact tests as appropriate. Problem with
missing hormonal data were minimal, with only a few subjects
missing one or two data points. Analyzing the data with and
without linear interpolation to fill in the occasional missing
values yielded similar results, therefore only the interpolated data
are reported. Before conducting any analyses, summary variables
for the hormonal measures and clinical rating scales were
examined for normality using the Shapiro and Wilks’W statistic.
The data were subject to log or square root transformation where
significantly nonnormal distributions were found. In cases where
no transformation normalized the data, nonparametric tests were
used. The following summary values were used to characterize
children’s GH responses: baseline, peak, and mean post-GH. The
baseline values were computed by determining the mean of the
three GH specimens taken at 230, 215, and 0 min preinfusion.
The peak value represents the highest value postinfusion, and the
mean post-GH values were the average of samples from 115
through 190 min. (The GH levels by 90 min were back to a level
that was not significantly different from baseline.) A comparison
using total GH, as computed by determining the area under the
curve with all GH values obtained from 0 to 90 min post-GH
using the trapezoidal rule revealed identical group comparisons;
only the mean values are reported here.
BIOL PSYCHIATRY
2000;48:981–988
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Table 1. Demographic Characteristics in Depressed and LowRisk Children
Variable
Age
Gender (F/M)
Race
(W/B/O)
SES
BMI
MDD
(n 5 82)
NC
(n 5 55)
11.2 6 1.7
29/53
11.2 6 1.8
22/33
66/15/1
39.2 6 13.9
19.4 6 3.6
49/3/3
47.8 6 11.1
18.8 6 4.1
Statistic
t(135) 5 0.11
x2 5 0.14
Fisher exact test
t(127) 5 3.68
t(135) 5 1.20
p
value
ns
ns
.0314
.0003
ns
Values are means 6 SDs. MDD, major depressive disorder; NC, normal
controls; Subjects; F/M, female/male; W/B/O, white/black/other; SES, socioeconomic status; BMI, body mass index.
Reliability Study
To assess the test–retest reliability of the GHRH test, the protocol
was repeated in 11 normal control subjects within 1 to 2 months
after the initial study.
Recovery Study
In the clinical follow-up of the depressed sample, subjects were
invited to participate in a repeat study when they had recovered
from the depressive episode. To be considered recovered, depressed children were required to be fully remitted for 8
consecutive weeks (Frank et al 1991) and medication free for at
least 8 weeks. At the time of these analyses, n 5 20 subjects had
been restudied in the same protocol following remission and had
their data compared with the findings from GH data obtained in
the depressed state.
Results
There were no significant group differences in age, gender, body mass index, or Tanner stage of sexual maturation (Table 1). The groups were significantly different in
SES [39.2 6 SD 13.9 vs. 47.8 6 SD 11.1; t(127) 5
3.68, p 5 .0003].
Because SES was significantly different between MDD
and control groups, this variable was examined in relation
to the summary GH measures and was not found to be a
significant covariate for any of the GH measures. There
were also no significant differences in GH responses
between male and female subjects in any of these analyses; thus, male and females subjects were combined for all
comparisons. Analyses examining pubertal status (Tanner
stage) also showed no significant effect on GH response to
GHRH.
Depressed versus Normal Control Subjects
Baseline GH measures (230 215, and 0 min before
GHRH infusion) were not different between groups (0.4
ng/mL 6 SEM 0.05 vs. 0.4 6 0.05). Following infusion of
GHRH, the depressed subjects (n 5 82) secreted signif-
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R.E. Dahl et al
BIOL PSYCHIATRY
2000;48:981–988
Figure 1. Growth hormone response to growth hormone–releasing hormone (GHRH) in children and adolescents with major
depressive disorder (F; n 5 82) compared to low-risk normal
control subjects (E; n 5 55). Time 0 corresponds to the
infusion of GHRH. Values are in ng/mL and represent the
means 6 SEMs.
icantly less GH than control subjects (n 5 55) as
measured by peak levels [13.9 ng/mL 6 SEM 1.4 vs. 19.5
ng/mL 6 SEM 2.1; t(135) 5 2.6, p 5 .02], and mean
levels postinfusion [8.7 ng/mL 6 SEM 0.9 vs. 12.2 6 1.3;
t(135) 5 2.6, p 5 .01; Figure 1 and Table 2]. The
effect size for the between-group differences in GH
response based on the entire sample (n 5 82 MDD
subjects; n 5 55 control subjects) was 0.44; the effect
size when examining only the independent replication
sample (n 5 46 MDD subjects; n 5 37 control subjects)
was 0.39.
GH Results in Relation to Severity and Other
Clinical Symptoms
Figure 2. Growth hormone response to growth hormone–releasing hormone in low-risk normal control subjects restudied for
test–retest reliability. Values are in ng/mL and represent the
means 6 SEMs. F, time 1 (n 5 11); E, time 2 (n 5 11).
weeks), severity of depression (mean depression 12 score
from the K-SADS was 31.4 6 5.7), and comorbid symptoms of anxiety symptoms (53% of the depressed sample
had current or past anxiety). None of these analyses
showed any significant effect on GH response to GHRH
within the MDD sample.
Test–Retest Reliability
The GH response to GHRH showed an intraclass correlation (ICC) 5 .89 (peak) and r 5 .93 (mean post) within
the 11 subjects who underwent repeat testing within 2
months (Figure 2).
GH Responses following Clinical Recovery
We examined GH response to GHRH in relation to clinical
symptoms, including prior episodes of depression (15% of
the sample had a history of a past episode of depression),
duration of depression (mean duration was 42.4 6 36.8
Table 2. Demographic Characteristics and Growth Hormone
Response to GHRH and during Baseline in Depressed and
Low-Risk Children
Variable
MDD
(n 5 82)
NC
(n 5 55)
Statistic
p
value
GHRH
Baseline
Postinfusion
Peak postinfusion
0.4 6 0.05
8.7 6 0.9
13.9 6 1.4
0.4 6 0.05
12.2 6 1.3
19.5 6 2.1
t135 5 0.32
t135 5 2.59
t135 5 2.55
ns
.0107
.0119
All between-group comparisons on growth hormone were done using logtransformed growth hormone values; reported growth hormone values are means 6
SEMs. MDD, major depressive disorder; NC 5 normal control subjects; GHRH,
growth hormone–releasing hormone.
On restudy in a medication-free state, GH responses were
not significantly different than their previous values obtained during the episode of MDD; mean GH post-GHRH
was 9.21 6 10.82 versus 8.10 6 7.61 [t(19) 5 0.36, ns]
and peak GH post-GHRH was 13.40 6 14.78 versus
13.72 6 12.82 [t(19) 5 0.07, ns] in depressed and
remitted states respectively. As shown in Figure 3, the GH
response in the MDD-recovered group (n 5 20) remained significantly lower than the GH response in the
control group.
GH Responses in Relation to
Hypothalmic–Pituitary–Adrenal Axis Measures
The subjects in this study had also undergone measurements of cortisol and corticotropin (baseline and following
corticotropin-releasing hormone challenge); analyses
comparing summary hypothalmic–pituitary–adrenal axis
Growth Hormone in Child Depression
Figure 3. Growth hormone response to growth hormone–releasing hormone (GHRH) in children and adolescents with major
depressive disorder studied during medication-free remission
from depression (E; n 5 20) compared with low-risk normal
control subjects (F; n 5 55). Time 0 corresponds to the
infusion of GHRH. Values are in ng/mL and represent the
means 6 SEMs.
measures and GH measures revealed no significant correlations within the MDD or control samples.
Discussion
Because of the challenges in recruitment and performing
biological studies in children, psychobiological studies in
child psychiatry typically entail small clinical and control
samples. There is also an inherent bias toward publishing
studies that have found group differences, compared with
small-sample “negative” studies that are less likely to be
written-up and published. This classic “file-drawer problem” is particularly concerning in the arena of child
psychiatry.
Large controlled studies and independent replications
are infrequent but essential to moving the field forward.
This article establishes a large, independent replication of
low GH response to pharmacologic stimulation associated
with child depression, which was first reported in PuigAntich’s seminal papers (Puig-Antich et al 1984a, 1984b,
1984c, 1984d).
By examining a large sample of depressed children
(n 5 82) selected over a 10-year interval in a wellcontrolled study, the data in this article establish strong
support for the hypothesis that low GH response to GHRH
represents a neuroendocrine marker of affective illness in
children. Our study also establishes good test-retest reliability for the measure, and demonstrates continuity of low
GH response to GHRH in depressed children in clinical
remission.
There are also several limitations to these data to be
BIOL PSYCHIATRY
2000;48:981–988
985
considered. One issue that has not been addressed is the
specificity of the finding to depression. It is possible that
low GH is associated more generally with psychiatric or
emotional difficulties in childhood. Few studies have
examined GH responses to pharmacologic challenge in
other child psychiatric disorders. A recent study in children with anxiety using a clonidine challenge (Sallee et al
1998) reported increased GH responses in the anxious
children compared with control subjects. The sample in
that study also included children with obsessive-compulsive disorder, as well as other anxiety disorders. Furthermore, studies in adult samples have generally reported low
GH responses to several types of pharmacologic challenge, in depression and anxiety disorders (Coplan et al
1997; Holsboer 1995; Uhde et al 1986) including generalized anxiety disorder (Abelson et al 1991) social phobia
(Tancer et al 1993), and panic disorder (Charney et al
1987; Coplan et al 1997, in press; Nutt 1989; Rapaport et
al 1989). Many of the pharmacologic challenges in adult
studies, however, (particularly clonidine and yohimbe
challenges) were based on the assumption that researchers
were evaluating the integrity of noradrenergic sensitivity
and that GH was simply a marker.
Focusing more specifically on GHRH stimulation studies in psychiatry, a critical review by (Skare et al 1994)
discussed four replications showing low GH response to
GHRH in adult depression, as well as two failures to
replicate. These authors summarized the promising results
but raised several concerns, including 1) the variability of
GH response among control subjects, 2) the need to
consider the age and gender of the subjects, 3) the lack of
uniformity of procedures and measures, and 4) absence of
data in adult studies regarding the test–retest reliability
within subjects. It is important to note that among the
controlled studies reviewed in that paper, the sample sizes
ranged from n 5 7 to n 5 19 subjects with depression
and the total number of depressed adults is only n 5 80
(combining all studies). In contrast, our study contained
n 5 82 depressed children and n 5 55 control subjects.
In addition, we performed reliability tests, examined the
influences of age and gender carefully, and used uniform
procedures based on previous studies.
One study of GHRH in depressed adults (Gann et al
1995) published after the Skare review reported no differences in GH response to GHRH; however, the sample
contained only n 5 12 MDD subjects and n 5 12 control
subjects and reported the GH was 645 6 770 (area under
the curve) in the MDD subjects and 1031 6 279 in the
control subjects. Thus, that “negative” paper actually
found lower GH response to GHRH in the MDD group
with an effect size of 0.67 (comparable to our results) and
likely failed to find significant group differences because
of the small samples.
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R.E. Dahl et al
BIOL PSYCHIATRY
2000;48:981–988
Effects on Growth
The functional significance of lower GH response regarding growth processes is unclear. There were no significant
differences in height or weight between groups, and
preliminary measures of height velocity were not different
between groups. It is possible that any difference in GH
regulation in response to GHRH challenge is not reflected
in overall GH production or IGF-1 levels, and that it does
not have any functional impact on growth. On the other
hand, these effects may be subtle and below the threshold
of detection over short intervals of time because Pine et al
reported a slight but statistically significant reduction in
expected adult height in the follow-up of children with
anxiety disorders, but only in the females (Pine et al 1996).
Functional Significance and Mechanism of Action
Since our finding is stable following clinical recovery, one
possibility is that this represents some type of early “scar”
marker related to having had a depressive episode; however, other work by our research group (Birmaher et al
2000) shows evidence of low GH in children at high
familial risk of depression but without any clinical signs of
depression. In that study, the mean GH response in the
nondepressed “high-risk” sample (n 5 64) was 8.6
ng/mL 6 1.1, similar to the MDD sample (n 5 82) 8.7
ng/mL 6 0.9 with both groups significantly different from
the normal control subjects without family loading for
depression (n 5 55) at 12.2 ng/mL 6 1.3. Taken
together, these data are consistent with a model that low
GH response to GHRH represents a “trait” marker associated with the risk or vulnerability toward depression.
Further, the absence of any significant relationship of GH
response to severity of depression or duration of depression is also consistent with the concept of a trait marker.
Another possibility is that early stress or adverse social
experiences early in life may alter GH regulation and
confer greater risk of depression. Some animal studies
have found low GH response in monkeys and rodents that
were exposed to maternal separation early in life. Champoux et al 1989 reported low GH responses to pharmacologic challenge in nursery-reared infant rhesus macaques
at 37 days of age compared with mother-reared control
subjects (the nursery-reared monkeys also showed higher
rates of depressive like behaviors later in life (Champoux
et al 1989). Coplan et al (1998), studying bonnet macaques
raised in variable foraging demand (VFD) conditions
(Rosenblum et al 1994), found low GH response to
clonidine infusion in the VFD offspring that showed high
rates of anxious social behaviors and low exploration.
These VFD offspring were also found to have elevated
cerebrospinal fluid somatostatin (GH-inhibiting peptide)
(Coplan et al 1998). Most recently Plotsky’s research
group (Mason et al 1998) found blunted GH response to
clonidine infusion in rodents that had experienced 180min maternal separations early in life compared with
handled control rats. Taken together, the animal data are
consistent with the concept that low GH responses are
associated with early social stress, anxious behavioral
patterns, or both across several species.
Holsboer, drawing from findings in adult depression
and from animal work, has presented a model whereby the
mechanism of GH changes seen in depression may be
mediated by alterations in central corticotropin-releasing
factor (Holsboer 1995). Coplan et al (in press) reported
results consistent with this link by showing that GH
response to clonidine in the VFD monkeys was significantly correlated with corticotropin-releasing factor in the
cerebrospinal fluid of these monkeys.
Clearly, there are several important mechanistic questions regarding the changes in GH response associated
with depression and possibly with the risk for depression
early in life. Promising preliminary results from a nonhuman primate model showing stable individual differences
in GH response to GHRH and clonidine in young monkeys
and a correlation between low GH response and low
behavioral reactivity in a stranger-approach condition (K.
Coleman et al, unpublished data) present one promising
approach to explore the underlying mechanisms.
Summary
Low GH response to GHRH appears to be a trait marker of
depression that is evident and stable early in development.
The mechanism and functional significance of this marker
requires further investigation. Progress in understanding
these findings will likely require both clinical and basic
investigations into the neurobehavioral systems underpinning these alterations in GH regulation, including developmental and genetic influences and the possible effects of
early adverse experiences.
This work was supported by National Institute of Health Grant Nos.
PO1-MH41712 (NDR and colleagues) and KO2-MH01362 (RED). This
line of investigation was originally initiated under the direction of the late
Joaquim Puig-Antich, to whom this article is dedicated. The authors wish
to extend our appreciation to Laura Trubnick and her staff in the Sleep
Laboratory, Stacy Stull and the staff of the Neuroendocrine Laboratory,
the clinical interviewers, and the children and families who made this
study possible.
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Releasing Hormone in Child Depression
Ronald E. Dahl, Boris Birmaher, Douglas E. Williamson, Lorah Dorn, James Perel,
Joan Kaufman, David A. Brent, David A. Axelson, and Neal D. Ryan
Background: This study examined growth hormone (GH)
response to growth hormone–releasing hormone (GHRH)
in a large sample of depressed children compared with
normal control children. Within-subject comparisons were
also performed in control subjects to examine test–retest
reliability and in depressed children comparing episode
versus clinical recovery.
Methods: The sample included depressed children (n 5
82) and normal control children (n 5 55) group-matched
for age, gender, and pubertal status; the mean ages were
11.2 6 1.7 and 11.2 6 1.8 years, respectively. We gave
GHRH (0.1 mcg/Kg) at 9 AM, and serum GH levels were
determined every 15 min from 230 min through 190 min
of the GHRH infusion. A subgroup of normal control
subjects (n 5 11) repeated the protocol for test–retest
reliability within a 2-month interval. A subgroup of
depressed children (n 5 20) were restudied off all medications following full clinical remission from depression.
Results: The mean GH response to GHRH was significantly lower in the depressed group (8.7 ng/mL 6 SEM
0.9) compared with normal control children [12.2 ng/
mL 6 SEM 1.3; t(135) 5 2.59, p 5 .01 effect size 0.44].
The test–retest reliability of GH response to GHRH was
stable (intraclass correlation 5 .93 for mean post-GH).
The GH response to GHRH remained low in subjects
restudied during clinical remission from depression.
Conclusions: Depressed children show low GH response
to GHRH. The measure appears to be reliable, and the low
GH response continues following clinical remission. Further studies are needed to explore the mechanism and
relative specificity of this finding. Biol Psychiatry 2000;
48:981–988 © 2000 Society of Biological Psychiatry
Key Words: Depression, growth hormone, growth hormone–releasing hormone, development, children,
adolescents
From the Department of Psychiatry, University of Pittsburgh School of Medicine,
Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania (RED, BB,
DEW, LD, JP, DAB, DAA, NDR) and the Department of Psychiatry, Yale
University School of Medicine, New Haven, Connecticut (JK).
Address reprint requests to Ronald E. Dahl, M.D., University of Pittsburgh Medical
Center, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh PA 15213.
Received January 8, 2000; revised May 1, 2000; accepted May 18, 2000.
© 2000 Society of Biological Psychiatry
Introduction
P
rogress in understanding affective disorders over the
past decade increasingly has focused attention on
questions of maturational influences on biological systems
of interest. There has been considerable interest in 1) the
effects of early adverse experiences on later expression of
affective dysregulation, 2) the increasing rates of depression during adolescent development, 3) the emergence of
gender differences in rates of depression during adolescent
development, and 4) changes across childhood, adolescence, adulthood, and geriatrics in specific domains, such
as symptom profile, clinical course, genetic influences,
and treatment response. Broadly speaking, this work has
yielded some areas of maturational continuity, as well as
areas of developmental variation (Angold et al 1998;
Birmaher et al 1996a, 1996b; Garber et al 1993; Harrington et al 1994; Kovacs 1996; Puig-Antich et al 1993;
Rao et al 1995; Ryan et al 1987).
This theme of both similarities and differences across
child, adolescent, and adult depression also has been
evident in psychobiologic studies. For example, HPA-axis
alterations and electroencephalogram (EEG) sleep
changes associated with depression show considerable
maturational variance (Dahl 1996; Dahl et al 1991a,
1991b, 1992, 1994, 1996; Emslie et al 1994). In contrast,
low growth hormone (GH) response to pharmacologic
challenges seen in association with depression has shown
relative continuity across development, including depressed samples ranging from prepubertal children
through old age (Jarrett et al 1990, 1994; Lesch et al 1987,
1989; Meyer et al 1991; Puig-Antich et al 1984c, 1984d;
Ryan et al 1988, 1994; Siever et al 1992).
There is also preliminary evidence that this low GH
persists after clinical recovery (in a medication-free state)
in depressed children (Puig-Antich et al 1984d) and
following treatment for depression in adults (Jarrett et al
1994).
Recently, our research group has found that low GH
response to growth hormone–releasing hormone is also
evident in children and adolescents with no personal
history of depression but with high rates of affective
0006-3223/00/$20.00
PII S0006-3223(00)00932-X
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BIOL PSYCHIATRY
2000;48:981–988
illness in their families (Birmaher et al 2000). These
results have been considered within an emerging model
based on the hypothesis that low GH response to GHRH
represents a stable trait marker for affective illness—a
marker evident before the onset of depression, persisting
across episode and recovery, and independent of age and
maturational changes.
The studies reported in this paper address the basic
foundation for further investigations of this model, focusing on three specific aims: 1) to extend earlier findings of
low GH response to GHRH by comparing a large sample
of depressed children and well-matched control subjects
with careful assessment of psychiatric and family history
data, 2) to examine the reliability of GH responses to
physiologic stimuli (within-subject test–retest reliability),
and 3) to examine GH responses after clinical recovery
within a subset of depressed children studied initially
during a depressive episode.
Methods and Materials
Phase 1 and Phase 2 Studies
The data described in this paper include GH data collected in two
similar studies. The research facility, most of the personnel, GH
assay procedures, and design of the study up to and including the
GHRH test were identical. Phase 1 of the study included a larger
number of neuroendocrine tests after the GHRH test; a later
phase of the study had a shorter neuroendocrine protocol. The
GHRH data from n 5 36 children with major depressive
disorder (MDD) n 5 18 normal control subjects from phase 1
studies were included in a preliminary report (Ryan et al 1994).
All of the phase 2 data are new, and there is no overlap with any
previously reported GH data. The methods for the GHRH test
measures and protocol were identical across studies, and analyses
were performed showing that there was no effect of phase on any
of the GH measures being examined, thus the data were combined across phase 1 and phase 2 studies to maximize the power
to examine covariates and subgroup effects.
Recruitment and Inclusion–Exclusion Criteria
Depressed children were recruited from the inpatient and outpatient clinics at Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center. Normal control children were
recruited through advertisement and personal contacts. Informed
consent to participate in the study was obtained in accordance
with the University of Pittsburgh Institutional Review Board
guidelines. Inclusion criteria common for all subjects were that
they be 7 to 15 years of age and medically healthy. Children in
the depressed cohort were required to meet DSM-III-R criteria
for MDD. Additional exclusion criteria for the MDD cohorts
only included 1) concurrent DSM-III-R diagnosis of anorexia
nervosa, bulimia nervosa, autism, schizoaffective disorder, or
schizophrenia and 2) MDD chronologically secondary to conduct
disorder.
For the normal control subjects only, additional inclusion
R.E. Dahl et al
criteria included 1) no lifetime history of any psychiatric disorder
and 2) low familial risk for affective illness. In this study, low
familial risk for affective disorder was operationally defined as
having no first-degree relative with a lifetime episode of any
affective disorder or schizophrenia spectrum illness; no seconddegree relative with a lifetime history of recurrent, bipolar, or
psychotic depression, schizoaffective disorder, or schizophrenia;
and no more than 20% of second-degree relatives with a single
episode of MDD.
Exclusion criteria for both groups were 1) significant medical
illnesses, 2) medications (except acetaminophen) within 2 weeks
of the study, 3) inordinate fear of needles, 4) obesity (weight
greater than 150% of ideal body weight) or severe growth failure
(weight or height less than 3% of the National Health Statistic
Curve), and 5) mental retardation or the presence of a specific
learning disability.
DIAGNOSTIC ASSIGNMENT. Diagnostic assessments of the
depressed cohorts were completed by research assistants who
administered the Present Episode (Chambers et al 1985) and
Epidemiologic (Orvaschel and Puig-Antich 1987) versions of the
semistructured diagnostic interview, the Schedule for Affective
Disorders and Schizophrenia for School-Aged Children (KSADS). The diagnosis of MDD was made using DSM-III-R
criteria, with the presence of all positive symptoms confirmed by
a child psychiatrist or psychologist. For normal control subjects,
if an initial telephone screen of the family indicated preliminary
eligibility and interest, the child’s lifetime history of psychiatric
symptomatology was assessed using only the K-SADS-E (Orvaschel and Puig-Antich 1987). All symptom ratings were made
by interviewing the parent(s) first, then interviewing the child.
All children who participated in the study were reinterviewed
using a short version of the K-SADS at the time of the
psychobiological studies to confirm presence of depressive
symptomatology.
All interviews were carried out by trained research clinicians
blind to the subject’s clinical status under the supervision of child
psychiatrists (DA, BB) or a child psychologist (JK). Interrater
reliability for all diagnoses for our studies has been k $ .70.
Socioeconomic status (SES) was measured using the Hollingshead four-factor index (Hollingshead 1975).
GHRH TEST. Following a visit and orientation to the laboratory, children and family members arrived in the lab to begin
the psychobiological study at 5 PM. The sleep–neuroendocrine
laboratory is furnished with many age-appropriate materials,
including books, art supplies, board games, entertainment videos,
and computer games. Children are given considerable individual
attention from staff with years of experience conducting biological studies with children. On a rating scale completed immediately after finishing the psychobiological studies, the majority of
children who participated in this and other studies conducted in
the lab rated the experience as “very positive” (Dahl and Ryan
1999).
An intravenous line was placed within the first hour of the
study, and children are then free to play interactive games, watch
movies, and so forth for the rest of the evening. Before bedtime,
EEG leads were placed for standard sleep recordings. On the
Growth Hormone in Child Depression
following morning, baseline blood samples for GH were obtained through the indwelling catheter at 8:30, 8:45, and 9:00 AM.
Immediately following the 9:00 AM draw, children received an
infusion of 1.0 mcg/kg of GHRH over 2 min. There were no
significant side effects of any sort related to the GHRH test.
Children generally showed no signs of behavioral reaction of any
kind. A physician was in attendance throughout the procedure.
Following GHRH administration, blood samples for GH were
obtained every 15 min for a total of 90 min. The child remained
fasting from bedtime (of the previous evening) until completion
of the GHRH test.
BLOOD SAMPLES AND GH ASSAYS. Blood samples were
collected in plastic tubes containing edetic acid (EDTA) then
centrifuged immediately in a refrigerated centrifuge. Plasma was
separated and stored at 280°C until assayed. Human growth
hormone levels were measured on a 50 mL plasma sample, run in
duplicate. A modified version of the double antibody 125I
radioimmunoassay procedure developed by Diagnostic Products
Corporation (Los Angeles) was used for these determinations. To
increase the sensitivity of the assay to 0.5 ng/mL of growth
hormone from that of the straight kit procedure, the amount of
antibody was decreased, and a longer, sequential incubation of
the antibody and radiolabeled antigen was used. Subjects’
duplicates with a coefficient of variation exceeding 5.0% were
retested. The range for the intraassay variation of subjects’
sample duplicates was 0.00 to 4.98% CV, with a mean of 0.87%
CV. Interassay variation ranged from 20.15% CV (mean of 2.47
ng/mL) to 13.68% CV (mean of 12.31 ng/mL).
Statistical Analyses
Sample characteristics were compared using analyses of variance, x2, and Fisher’s exact tests as appropriate. Problem with
missing hormonal data were minimal, with only a few subjects
missing one or two data points. Analyzing the data with and
without linear interpolation to fill in the occasional missing
values yielded similar results, therefore only the interpolated data
are reported. Before conducting any analyses, summary variables
for the hormonal measures and clinical rating scales were
examined for normality using the Shapiro and Wilks’W statistic.
The data were subject to log or square root transformation where
significantly nonnormal distributions were found. In cases where
no transformation normalized the data, nonparametric tests were
used. The following summary values were used to characterize
children’s GH responses: baseline, peak, and mean post-GH. The
baseline values were computed by determining the mean of the
three GH specimens taken at 230, 215, and 0 min preinfusion.
The peak value represents the highest value postinfusion, and the
mean post-GH values were the average of samples from 115
through 190 min. (The GH levels by 90 min were back to a level
that was not significantly different from baseline.) A comparison
using total GH, as computed by determining the area under the
curve with all GH values obtained from 0 to 90 min post-GH
using the trapezoidal rule revealed identical group comparisons;
only the mean values are reported here.
BIOL PSYCHIATRY
2000;48:981–988
983
Table 1. Demographic Characteristics in Depressed and LowRisk Children
Variable
Age
Gender (F/M)
Race
(W/B/O)
SES
BMI
MDD
(n 5 82)
NC
(n 5 55)
11.2 6 1.7
29/53
11.2 6 1.8
22/33
66/15/1
39.2 6 13.9
19.4 6 3.6
49/3/3
47.8 6 11.1
18.8 6 4.1
Statistic
t(135) 5 0.11
x2 5 0.14
Fisher exact test
t(127) 5 3.68
t(135) 5 1.20
p
value
ns
ns
.0314
.0003
ns
Values are means 6 SDs. MDD, major depressive disorder; NC, normal
controls; Subjects; F/M, female/male; W/B/O, white/black/other; SES, socioeconomic status; BMI, body mass index.
Reliability Study
To assess the test–retest reliability of the GHRH test, the protocol
was repeated in 11 normal control subjects within 1 to 2 months
after the initial study.
Recovery Study
In the clinical follow-up of the depressed sample, subjects were
invited to participate in a repeat study when they had recovered
from the depressive episode. To be considered recovered, depressed children were required to be fully remitted for 8
consecutive weeks (Frank et al 1991) and medication free for at
least 8 weeks. At the time of these analyses, n 5 20 subjects had
been restudied in the same protocol following remission and had
their data compared with the findings from GH data obtained in
the depressed state.
Results
There were no significant group differences in age, gender, body mass index, or Tanner stage of sexual maturation (Table 1). The groups were significantly different in
SES [39.2 6 SD 13.9 vs. 47.8 6 SD 11.1; t(127) 5
3.68, p 5 .0003].
Because SES was significantly different between MDD
and control groups, this variable was examined in relation
to the summary GH measures and was not found to be a
significant covariate for any of the GH measures. There
were also no significant differences in GH responses
between male and female subjects in any of these analyses; thus, male and females subjects were combined for all
comparisons. Analyses examining pubertal status (Tanner
stage) also showed no significant effect on GH response to
GHRH.
Depressed versus Normal Control Subjects
Baseline GH measures (230 215, and 0 min before
GHRH infusion) were not different between groups (0.4
ng/mL 6 SEM 0.05 vs. 0.4 6 0.05). Following infusion of
GHRH, the depressed subjects (n 5 82) secreted signif-
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R.E. Dahl et al
BIOL PSYCHIATRY
2000;48:981–988
Figure 1. Growth hormone response to growth hormone–releasing hormone (GHRH) in children and adolescents with major
depressive disorder (F; n 5 82) compared to low-risk normal
control subjects (E; n 5 55). Time 0 corresponds to the
infusion of GHRH. Values are in ng/mL and represent the
means 6 SEMs.
icantly less GH than control subjects (n 5 55) as
measured by peak levels [13.9 ng/mL 6 SEM 1.4 vs. 19.5
ng/mL 6 SEM 2.1; t(135) 5 2.6, p 5 .02], and mean
levels postinfusion [8.7 ng/mL 6 SEM 0.9 vs. 12.2 6 1.3;
t(135) 5 2.6, p 5 .01; Figure 1 and Table 2]. The
effect size for the between-group differences in GH
response based on the entire sample (n 5 82 MDD
subjects; n 5 55 control subjects) was 0.44; the effect
size when examining only the independent replication
sample (n 5 46 MDD subjects; n 5 37 control subjects)
was 0.39.
GH Results in Relation to Severity and Other
Clinical Symptoms
Figure 2. Growth hormone response to growth hormone–releasing hormone in low-risk normal control subjects restudied for
test–retest reliability. Values are in ng/mL and represent the
means 6 SEMs. F, time 1 (n 5 11); E, time 2 (n 5 11).
weeks), severity of depression (mean depression 12 score
from the K-SADS was 31.4 6 5.7), and comorbid symptoms of anxiety symptoms (53% of the depressed sample
had current or past anxiety). None of these analyses
showed any significant effect on GH response to GHRH
within the MDD sample.
Test–Retest Reliability
The GH response to GHRH showed an intraclass correlation (ICC) 5 .89 (peak) and r 5 .93 (mean post) within
the 11 subjects who underwent repeat testing within 2
months (Figure 2).
GH Responses following Clinical Recovery
We examined GH response to GHRH in relation to clinical
symptoms, including prior episodes of depression (15% of
the sample had a history of a past episode of depression),
duration of depression (mean duration was 42.4 6 36.8
Table 2. Demographic Characteristics and Growth Hormone
Response to GHRH and during Baseline in Depressed and
Low-Risk Children
Variable
MDD
(n 5 82)
NC
(n 5 55)
Statistic
p
value
GHRH
Baseline
Postinfusion
Peak postinfusion
0.4 6 0.05
8.7 6 0.9
13.9 6 1.4
0.4 6 0.05
12.2 6 1.3
19.5 6 2.1
t135 5 0.32
t135 5 2.59
t135 5 2.55
ns
.0107
.0119
All between-group comparisons on growth hormone were done using logtransformed growth hormone values; reported growth hormone values are means 6
SEMs. MDD, major depressive disorder; NC 5 normal control subjects; GHRH,
growth hormone–releasing hormone.
On restudy in a medication-free state, GH responses were
not significantly different than their previous values obtained during the episode of MDD; mean GH post-GHRH
was 9.21 6 10.82 versus 8.10 6 7.61 [t(19) 5 0.36, ns]
and peak GH post-GHRH was 13.40 6 14.78 versus
13.72 6 12.82 [t(19) 5 0.07, ns] in depressed and
remitted states respectively. As shown in Figure 3, the GH
response in the MDD-recovered group (n 5 20) remained significantly lower than the GH response in the
control group.
GH Responses in Relation to
Hypothalmic–Pituitary–Adrenal Axis Measures
The subjects in this study had also undergone measurements of cortisol and corticotropin (baseline and following
corticotropin-releasing hormone challenge); analyses
comparing summary hypothalmic–pituitary–adrenal axis
Growth Hormone in Child Depression
Figure 3. Growth hormone response to growth hormone–releasing hormone (GHRH) in children and adolescents with major
depressive disorder studied during medication-free remission
from depression (E; n 5 20) compared with low-risk normal
control subjects (F; n 5 55). Time 0 corresponds to the
infusion of GHRH. Values are in ng/mL and represent the
means 6 SEMs.
measures and GH measures revealed no significant correlations within the MDD or control samples.
Discussion
Because of the challenges in recruitment and performing
biological studies in children, psychobiological studies in
child psychiatry typically entail small clinical and control
samples. There is also an inherent bias toward publishing
studies that have found group differences, compared with
small-sample “negative” studies that are less likely to be
written-up and published. This classic “file-drawer problem” is particularly concerning in the arena of child
psychiatry.
Large controlled studies and independent replications
are infrequent but essential to moving the field forward.
This article establishes a large, independent replication of
low GH response to pharmacologic stimulation associated
with child depression, which was first reported in PuigAntich’s seminal papers (Puig-Antich et al 1984a, 1984b,
1984c, 1984d).
By examining a large sample of depressed children
(n 5 82) selected over a 10-year interval in a wellcontrolled study, the data in this article establish strong
support for the hypothesis that low GH response to GHRH
represents a neuroendocrine marker of affective illness in
children. Our study also establishes good test-retest reliability for the measure, and demonstrates continuity of low
GH response to GHRH in depressed children in clinical
remission.
There are also several limitations to these data to be
BIOL PSYCHIATRY
2000;48:981–988
985
considered. One issue that has not been addressed is the
specificity of the finding to depression. It is possible that
low GH is associated more generally with psychiatric or
emotional difficulties in childhood. Few studies have
examined GH responses to pharmacologic challenge in
other child psychiatric disorders. A recent study in children with anxiety using a clonidine challenge (Sallee et al
1998) reported increased GH responses in the anxious
children compared with control subjects. The sample in
that study also included children with obsessive-compulsive disorder, as well as other anxiety disorders. Furthermore, studies in adult samples have generally reported low
GH responses to several types of pharmacologic challenge, in depression and anxiety disorders (Coplan et al
1997; Holsboer 1995; Uhde et al 1986) including generalized anxiety disorder (Abelson et al 1991) social phobia
(Tancer et al 1993), and panic disorder (Charney et al
1987; Coplan et al 1997, in press; Nutt 1989; Rapaport et
al 1989). Many of the pharmacologic challenges in adult
studies, however, (particularly clonidine and yohimbe
challenges) were based on the assumption that researchers
were evaluating the integrity of noradrenergic sensitivity
and that GH was simply a marker.
Focusing more specifically on GHRH stimulation studies in psychiatry, a critical review by (Skare et al 1994)
discussed four replications showing low GH response to
GHRH in adult depression, as well as two failures to
replicate. These authors summarized the promising results
but raised several concerns, including 1) the variability of
GH response among control subjects, 2) the need to
consider the age and gender of the subjects, 3) the lack of
uniformity of procedures and measures, and 4) absence of
data in adult studies regarding the test–retest reliability
within subjects. It is important to note that among the
controlled studies reviewed in that paper, the sample sizes
ranged from n 5 7 to n 5 19 subjects with depression
and the total number of depressed adults is only n 5 80
(combining all studies). In contrast, our study contained
n 5 82 depressed children and n 5 55 control subjects.
In addition, we performed reliability tests, examined the
influences of age and gender carefully, and used uniform
procedures based on previous studies.
One study of GHRH in depressed adults (Gann et al
1995) published after the Skare review reported no differences in GH response to GHRH; however, the sample
contained only n 5 12 MDD subjects and n 5 12 control
subjects and reported the GH was 645 6 770 (area under
the curve) in the MDD subjects and 1031 6 279 in the
control subjects. Thus, that “negative” paper actually
found lower GH response to GHRH in the MDD group
with an effect size of 0.67 (comparable to our results) and
likely failed to find significant group differences because
of the small samples.
986
R.E. Dahl et al
BIOL PSYCHIATRY
2000;48:981–988
Effects on Growth
The functional significance of lower GH response regarding growth processes is unclear. There were no significant
differences in height or weight between groups, and
preliminary measures of height velocity were not different
between groups. It is possible that any difference in GH
regulation in response to GHRH challenge is not reflected
in overall GH production or IGF-1 levels, and that it does
not have any functional impact on growth. On the other
hand, these effects may be subtle and below the threshold
of detection over short intervals of time because Pine et al
reported a slight but statistically significant reduction in
expected adult height in the follow-up of children with
anxiety disorders, but only in the females (Pine et al 1996).
Functional Significance and Mechanism of Action
Since our finding is stable following clinical recovery, one
possibility is that this represents some type of early “scar”
marker related to having had a depressive episode; however, other work by our research group (Birmaher et al
2000) shows evidence of low GH in children at high
familial risk of depression but without any clinical signs of
depression. In that study, the mean GH response in the
nondepressed “high-risk” sample (n 5 64) was 8.6
ng/mL 6 1.1, similar to the MDD sample (n 5 82) 8.7
ng/mL 6 0.9 with both groups significantly different from
the normal control subjects without family loading for
depression (n 5 55) at 12.2 ng/mL 6 1.3. Taken
together, these data are consistent with a model that low
GH response to GHRH represents a “trait” marker associated with the risk or vulnerability toward depression.
Further, the absence of any significant relationship of GH
response to severity of depression or duration of depression is also consistent with the concept of a trait marker.
Another possibility is that early stress or adverse social
experiences early in life may alter GH regulation and
confer greater risk of depression. Some animal studies
have found low GH response in monkeys and rodents that
were exposed to maternal separation early in life. Champoux et al 1989 reported low GH responses to pharmacologic challenge in nursery-reared infant rhesus macaques
at 37 days of age compared with mother-reared control
subjects (the nursery-reared monkeys also showed higher
rates of depressive like behaviors later in life (Champoux
et al 1989). Coplan et al (1998), studying bonnet macaques
raised in variable foraging demand (VFD) conditions
(Rosenblum et al 1994), found low GH response to
clonidine infusion in the VFD offspring that showed high
rates of anxious social behaviors and low exploration.
These VFD offspring were also found to have elevated
cerebrospinal fluid somatostatin (GH-inhibiting peptide)
(Coplan et al 1998). Most recently Plotsky’s research
group (Mason et al 1998) found blunted GH response to
clonidine infusion in rodents that had experienced 180min maternal separations early in life compared with
handled control rats. Taken together, the animal data are
consistent with the concept that low GH responses are
associated with early social stress, anxious behavioral
patterns, or both across several species.
Holsboer, drawing from findings in adult depression
and from animal work, has presented a model whereby the
mechanism of GH changes seen in depression may be
mediated by alterations in central corticotropin-releasing
factor (Holsboer 1995). Coplan et al (in press) reported
results consistent with this link by showing that GH
response to clonidine in the VFD monkeys was significantly correlated with corticotropin-releasing factor in the
cerebrospinal fluid of these monkeys.
Clearly, there are several important mechanistic questions regarding the changes in GH response associated
with depression and possibly with the risk for depression
early in life. Promising preliminary results from a nonhuman primate model showing stable individual differences
in GH response to GHRH and clonidine in young monkeys
and a correlation between low GH response and low
behavioral reactivity in a stranger-approach condition (K.
Coleman et al, unpublished data) present one promising
approach to explore the underlying mechanisms.
Summary
Low GH response to GHRH appears to be a trait marker of
depression that is evident and stable early in development.
The mechanism and functional significance of this marker
requires further investigation. Progress in understanding
these findings will likely require both clinical and basic
investigations into the neurobehavioral systems underpinning these alterations in GH regulation, including developmental and genetic influences and the possible effects of
early adverse experiences.
This work was supported by National Institute of Health Grant Nos.
PO1-MH41712 (NDR and colleagues) and KO2-MH01362 (RED). This
line of investigation was originally initiated under the direction of the late
Joaquim Puig-Antich, to whom this article is dedicated. The authors wish
to extend our appreciation to Laura Trubnick and her staff in the Sleep
Laboratory, Stacy Stull and the staff of the Neuroendocrine Laboratory,
the clinical interviewers, and the children and families who made this
study possible.
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