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Growth hormone secretion during sleep in male depressed patients
Pmg.
NeumPsyclmphwmanl.
& Bbl.
Psychht.
1996,
CopyrightQ
1998
Vol. 22.
pp. 467463
Elsevier SdenceInc.
Pdnted IntheUSA. Allrightsreserved 027%5646/96 PII
$19.00
+ .oO
t30275-5546(98)00019-9
GROWTH HORMONE SECRETION DURING SLEEP IN MALE DEPRESSED PATIENTS PAVLOS N. SAKKAS, CONSTANTIN R. SOLDATOS, JOANNE D. BERGIANNAKI, THOMAS J. PAPARRIGOPOULOS and COSTAS N. STEFANIS
Department
of Psychiatry, University of Athens, Greece.
( Final form. December
1997)
Abstract Sakkas, Pavlos N., Constantin R. Soldatos, Joanne D. Bergiannaki, Thomas J Paparrigopoulos and Costas N. Stefanis: Growth hormone secretion during sleep in male depressed patients. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1998, 22,pp.467-463.01998 ElsevierScienceInc. 1.
2. 3.
4.
Growth hormone (GH) secretion during sleep was studied in ten male patients with major depression according to DSM III and eight normal controls. Samples were collected through a continuous blood withdrawal pump while sleep was recorded in the laboratory. The results showed a marked decrease in the GH secretion mainly during the first three hours of sleep in depressed patients as compared to normal controls. DST and TRH tests were also administered to the same patients but no correlation was observed between a positive test and a blunted GH secretion, suggesting that the various neuroendocrinological disturbances do not coexist in all depressed patients. This disturbance in GH secretion during sleep, along with reduced slow wave sleep (SWS), gives support to the theory that GHRH is the common stimulus of SWS and GH release and that the ratio of GHRH and its counterpart CRH plays a major role in the pathophysiology of disturbed endocrine activity during sleep in depression.
Keywords: depression,
growth hormone, sleep, slow wave sleep.
Abbreviations: corticotropin releasing hormone (CRH), dexamethasone suppression test (DST), growth hormone (GH), growth hormone releasing hormone (GHRH), Hamilton depression rating scale (HDRS), luteinizing hormone releasing hormone (LHRH), rapid eye movements (REM), rapid eye movements latency (REM-L), slow wave sleep (SWS), thyrotropin releasing hormone (TRH), thyroid stimulating hormone (TSH).
467
P.N. Sakkas
et al
Introduction
Sleep is a powerful first two hours
physiologic
secreted in normal individuals GH secretion
stimulus
70-90s
of sleep,
with SWS
et al 1991, Van Cauter that no definitive SWS production
related
to the first non-REM period
et al 1992). Although
it was
in animals
et al 1988, Steiger
sleep
characteristic,
and in humans
albeit non-specific, mainly
and sleep architecture,
(Gillin 1983, Reynolds and Kupfer 1996).
patients
depressed
believed
(Sassin et al 1969, Karacan et al 1971) indicate
depressed
disturbances
patients
in their sleep
during the first 2-3 hours of
1987, Benca et al 1992; Soldatos
Furthermore, lower
show
that GHRH is the
(Ehlers et al 1986, Obal
et al 1992). On the other hand,
Paparrigopoulos
and
initially
answer could be given whether nocturnal GH release and
common stimulus of GH release and SWS production
efficiency
the
of GH is
(Takahashi et al 1968, Honda et al 1969, Ho11
are interdependent
more recent findings
manifest
during
24 hour amount
(Takahashi et al 1968). This sleep related
seems to be temporally
and particularly
for GH secretion;
of the total
it
is
responses
well
to
established
some
that
pharmacological
challenges of GH secretion as compared to normal controls
(Matussek et al
1980, Checkley et al 1981, Lesch et al 1987, Ansseau et al 1988, Laakmann et al 1990, Siever et al 1992, Holsboer 1995). Based
on
expectable GH
the
above,
depressed
patients
compared
to normal
in
rather
GH
in
secretion
depressed
pioneering
GH
peaks
secreted
hormonal
with
are
rather
secretion when
of
patients
(Schilkrut et al 1975). These
discrepant
results.
in depressed
during similar
sleep
few studies of
six were
findings were
studies of depressives both during the acute and 1993). Thus,
patients
Other in
was
sleep, amounts
when
secretion,
during the first 120-200 minutes
a
reduction
et al
during waking
patients
an overall
of sleep was found
diurnal
(Mendlewicz
in other reports
significant
however,
studies,
occurred
depressed
of GH despite
group. Nonetheless,
studies,
two
found
et al 1988). This hypersecretion
than
during
patients,
study,
nocturnal
(Steiger et al 1989,
of GH
SWS in the patient nocturnal
a
decreased
controls
state
1985, Linkowski
controls
showed
rather
hypersecretion
hours
In
in subsequent
the remitted resulted
sleep
results.
of
Yet, there have been relatively
during
secretion
contradictory
replicated
abnormalities
in depression.
and
reduction
focusing in
normal
GH
in
on the release
(Jarrett et al 1985,
Growth hormone secretion during sleep in depression
1990a,
Voderholzer
1994;
sample of depressed basal
nocturnal
(Rubin
et
pituitary
al
its overall
patients
GH
1993).
Our
in depressed
in
has
largest
showed no difference
responses
to
TRH
nocturnal
or
in
LHRH
secretion
(Stefanis et al 1985b).
on nocturnal
tests
of the
of
(Stefanis et al 1985a) as well as
profile
are presented.
other psychoendocrinological
GH
studied
depression
our findings
patients
or
group
in major
neuroendocrinological
present paper,
a study
Finally,
and normal controls
concentrations
1990).
hormones
et al
469
GH secretion
Also
In the
and sleep patterns
presented
are the
results
of
(DST and TRH) in the same individuals.
Methods
Subjects
Nocturnal
GH
secretion
patients
and
consents
were
patients
ranged between
22
59;
and
eight
obtained
the
significantly
was
normal
measured
controls.
before
they
during
All
sleep
subjects
entered
the
in
ten
were
depressed
male;
study.
The
informed
age
of
the
22 and 67, while that of normal controls between
mean
*SD
age
(40.9 + 14.1
of
the
for patients
two vs
groups
37.5
did
* 14.3
not
for
differ
controls).
Patients and controls were free of any physical
illness during the period
of
they
the
study,
and
endocrinological psychiatric drug
free
patients period; their
disorder.
history. for
their
at
Controls
Six patients
least
received
personal
15
small
days
fixed
history were
free
as well
as
before doses
IDS
Table
patients
Department Hospital
on
of
with
1) were
and
of
the diagnosis the
study
of
the
in
4) the
depression
(mean duration
weeks; mean number of previous
any
not past
normal the
report or
present
controls
study.
any
Only
during
were four this
(patients 1,5, and 6 as per
University
of major
did
benzodiazepines
(patient
hospitalised
Psychiatry
entering
one
of all
entering
three of them 1Omg of diazepam daily
depressed
before
in
3mg
of
bromazepam.
inpatient of
Athens
unit
of
The the
at
Eginition
for at least
two weeks
of present
episodes 1.7 f 1.4).
episode
5.1 f
1.2
P.N. Sal&as et a&
Assessments diagnosis
The
established
of
in all ten patients
10 as per their the
affective
major
criteria
IDS on Table of
1) by two independent (American
DSM-III
their depressive
Furthermore, item Hamilton
Depression
disorder-depressed
psychiatrists
Psychiatric
symptomatology
Rating Scale
Association
was evaluated
was 5 and using
1980).
using the 21-
(HDRS) (Hamilton 1960); only those
who scored above 22 were included in the study 32.2 + 9.16). These patients
episode
(two with bipolar illness, patients
(their mean score rt SD was
had no other current diagnoses
on axis I of
the DSM III. Three
to seven
DST following
days before
the sleep
standard procedures
study,
all patients
underwent
a
(Carroll et al 1981). Eight of them had
also a TRH test on the day before the DST; they were injected with 400pg of synthetic min
after
TRH and their TSH response was measured
the
increase of plasma
test
was
to its baseline value
the TRH
evaluated
30, 60, 90, and 120 as
blunted
when
the
level of TSH after the infusion of TRH, was less than
6uU/ml as compared patients
This
injection.
test was
(Loosen and Prange 1982). In two
not completed
for technical
reasons.
None
of
the controls had a DST or TRH test during the study. The sampling while
of GH secretion recorded
were
subjects
technique
(Rechtschaffen
instructed
to
wakefulness
and
potentially adaptation not
diet
psychoactive night before
considered
to
be
shown to be practically 1967, Sakkas
using Kales
All
previous
and
substances. the actual
necessary,
lights through
were
turned
polysomnographic our
to the
abstain
from
subjects
study,
For both study
because
alcohol groups
adaptation
were
a sleepthe night
to have a regular and
other
there was no
study night. An adaptation
absent in depressed patients
One to three hours before
laboratory
to that of the day preceding
schedule
1974, Browman and Cartwright
connected
of
Further, they were instructed
et al 1990) as well as in normal
p.m. when
in the sieep
standard
the
1968).
the week
comparable
spent in the laboratory. rest-activity
and
during
follow,
schedule
was accomplished
effects
night was have
been
(Mendels and Hawkins
individuals
(Coble et al
1980). an E-hour sleep recording off to about
a nonthrombogenic
6.30 a.m.)
(from about 10.30 every
subject
was
cannula and a long blood catheter to
Growth hormone secretion during sleep in depression an ambulatory test tube adjacent
continuous
withdrawal
pump
471
the blood
leading
sample
(Kowarski et al 1971). Using this pump, which was located in an room
the authors
were
able without
take hourly blood samples throughout
disturbing
the
the night by changing
subjects
hour
of
each
blood
which
fluctuations
sample have
may
collection
controlling
since
occurred
collection. All blood samples were immediately was
frozen
at
radioimmunoassay the evaluation l
since
-25C"
the hormonal
were
GH
sample
and the plasma
determined
using
of this method was 0.3ng/ml.
Baseline value of GH level. As such, the authors considered during the 1-3 hour period before
of the sleep recording. to
any
a
For
of GH secretion we used the following measures:
value of GH secretion
tried
during the
for
previous
centrifuged
levels
the sensitivity
method;
the
to
the test tube
every hour. Thus, the mean GH secretory rate could be measured whole
to a
avoid
By choosing
as much
the lowest pre-sleep
as possible
the
effect
on GH
the lowest
the beginning GH value, we levels
of
the
stress related to the cannulation procedure. l
Maximal
GH
level
sleep,
during
as
it
was
determined
in
the
blood
samples after sleep onset. l
Total GH secretion during sleep time, represented plasma
GH
curve.
We
estimated
this
area
by
as the area under the
multiplying
the
GH
mean
value of each hour by the minutes spent asleep after sleep onset during this hour of the night. l
GH
secretion
during
estimated measuring
the
first
three
hours
of
sleep,
which
was
also
the area under the plasma GH curve that corresponds
to the first three hours after sleep onset. Polysomnographic standardized
data
procedures
objective assessment and
SWS
was
established 1, having
were
scored
of wakefulness
obtained
for
each
with the appearance a duration
using
(Rechtschaffen
30
and
set
Kales
epochs 1968).
based
on
Thus,
an
as well as REM and sleep stages 1, 2,
subject
night.
The
onset
of
sleep
was
of any stage of sleep, other than stage
of one minute
or greater.
sleep was stage 1, it had to be followed without
If the initial any intervening
stage of wake by
at least one minute of either stage 2,3,4 or REM. REM latency was defined in
terms
of
minutes
elapsed
from
sleep
onset
occurrence of the first REM epoch, subtracting wakefulness.
to
REM
onset
i.e.
the
the minutes of intervening
472
P.N. Sakkas et cd_
Data Analysis
The data were
analyzed
using
Student's
t-test
and
Pearson's
product-
moment correlation.
GH nglml 0\1=8)
_T. I
( ’ (N=S)
(N=8}
6-
T’
/T,
- 5-
/
I--
l0
I 1
I 2
I 4
I 3
I‘
I 5
-
T-@ I
6
7
8
Time lapsed from Sleep Onset (hours) and normal Fig 1. GH secretion curves of depressed patients (_) controls (---) during nocturnal sleep. Each curve depicts the mean hourly GH levels + SD.
Results Overall GH secretory patterns Figure 1 shows the overall and normal controls the
sleep
pattern
onset.
There
of the two
increased
secretion
was
study of
GH
secretion
during
the
a
clear-cut
groups. during
whereas the depressed patients GH
GH secretory
pattern
of depressed
during the night. The reference
same
Normal the
point
difference controls
first
3-4
of
sleep.
the
manifested hours
showed a less pronounced hours
in
GH
of
patients
(0) represents secretory a markedly
their
sleep,
increase in their
secretion
and
sleep
Growth hormone secretion during sleep in depression
parameters
patients
depressed
of
individually
and
473
controls
normal
shown
are
on Table 1 and in terms of mean values on Table 2.
Table 1
GH Secretion and Other Sleep and Psychoendocrinological Parameters of Depressed Patients and of Normal Controls.
I.D.
REM-L"
GH/3ha
Age
DST
SWS/3h"
TRH
HDRS
Depressed patients 1 2 3 4 5 6 7 8 9 10
43 67 45 49 22 42 25 23 42 51
44 162 234 258 267 336 341 644 1170 1380
19 49 15 21 81 48 59 186 126 44
0 0 0 0 6 12 34 11 4 2
+
41 26 24 24 30 22 21 38 43 41
+ + +
+ t
+ + t
Normal controls 50 32 32 26 22 59 26 53
1
2 3 4 5 6 7 8
240 618 732 842 948 1255 1380 2124
14 37 51 64 72 12 14 21
100
15 91
66 58 64 85 81
'GH/3h: GH secretion during the first 3 hours of sleep (min ng/mg); L'~~~L: REM latency (min); 'SWS/3h: SWS during the first 3 hours of sleep (min)
As Table 2 shows, there was no significant baseline and highest two groups. lower
total
(p
GH
However, amount
there was a trend for depressed of
Furthermore, during
growth the
hormone
difference
secretion between
in terms of both
during
the
as presented
first
three
patients
during
patients
the first three hours of sleep
secretion
individually,
difference
sleep levels of growth hormone secretion between the
and
in Table 1, relatively
of
sleep
sleep
controls
(pcO.05). When
hours
to have a
nocturnal
was
the values
were
observed
little overlap of these
P.N.Sal&as etal.
474
values between
the two groups was found. Only one normal control's value
was below a cut-off values
patients' diagnostic
point
of 500 min x ng/ml while just three depressed
exceeded of
sensitivity
it.
Consequently,
this
based
measurement
is
on
this
70YJ and
its
sample
the
specificity
81.5%. Table 2
Sleep Patterns and GH Secretion: Depressed Patients vs Controls
Depressed
Controls
10
8 37.5 rt 14.3
N
Age
40.9 f 14.1
t-test
Sleep Characteristics" Total sleep time Total REM time REM latency Total SWS time SWS time/3h
261.6 rt 103 52.9 k 23.2 65.4 f 41.1 17.0 + 26.4 6.9 k 10.6
304.5 62.0 78.2 61.7 43.9
k + + + k
NS
14,6 28.3 27.5 27.2 25.0
NS NS
PC.01 PC.01
GH secretion parameters Baseline levelb Highest sleep levelb Total sleep secret.' Secret./first 3hrs' "Time in minutes;
Sleep patterns In
terms
difference time, total
no
as
depressed REM
well
as
between
rate during
the
of
and
data analysis
correlation amount
polysomnographic
0.7 9.4 1469.2 1017.3
NS
!L 0.2 _+ 5.6 f 663.0 + 572.4
for
between wave
there
NS
PC.1 p<.o5
in min x ng/ml
and controls (Table 2).
the
first
was
no
significant
regarding
total sleep
Slow
three
wave
hours
within
the depressed
amount
of
group,
age
and
sleep
slow
there growth
sleep of
wave
was
no
hormone
(r=-0.61)
during
for
sleep
group that in the controls.
the was
However,
group showed that there is sleep
and
the three first hours of sleep
depressed
slow
data,
patients latency
less in the depressed
correlation
secretion within
the
between
individual
0.3 4.5 631.0 437.0
bGH values in ng/ml; 'The GH secretion
REM minutes night
* + k f
& GH secretion
of
significantly
0.5 6.0 915.9 487.0
growth
statistically secretion the
hormone
(r=0.03). Moreover,
first
rate
significant (r=0.02) or
three
hours
of
Growth hormone secretion during sleep in depression
the
sleep;
correlation,
latter
sample,
is
quite
strong.
between
the amount
non-significant
albeit
Furthermore,
or the percentage
no
475
for
correlation
could
of any particular
sleep
our
small
be
found
stage and
the GH secretory activity at any period of sleep. Other neuroendocrinological
tests
Seven out of ten patients
had an abnormal
the two psychoendocrinological not adequately
sleep and response
depressive
TSH response
between
no correlation
response
in at least one of
(Table 1). Dexamethasone
could
suppress cortisol secretion in five patients while four of
them had a blunted correlation
tests used
GH
to TRH. As Table
hyposecretion
during
the
1 shows, there was no first
three
hours
of
in either the DST or the TRH test. Finally, there was
between
any value of the GH secretion and severity of the
symptomatology
as measured
by
the
either
HDRS,
in terms
item scores. Even the strongest
total score or of individual
of
correlation
(r=0.5) which was found between GH secretion during the first three hours of sleep and total HDRS score was not statistically
significant
evidently
due to the small sample size.
Discussion Nocturnal GH secretion in depression The most notable result of the present study is the clear-cut in
GH
nocturnal
secretion
in
depressed
patients
compared
decrease
with
normal
controls, mainly during the first part of the night. Previous studies had shown that nocturnal
GH secretion
et al 1975, Steiger
et al 1989, 1993; Jarrett
Voderholzer
in depressives
et al 1993), or similar
may be lower
et al 1985,
(Schilkrut
1990a,
1994;
(Mendlewicz et al 1985, Linkowski
et
al 1988; Rubin et al 1990) to that of normal controls. Of these studies, in only one a large sample was employed
(Rubin et al 1990). However,
in
that study, which is at variance with ours, both male and female subjects were
included
utilized.
and
On the
a
other
blood-sampling hand,
method
different
it is noteworthy
that
our
than
ours
results
was
are
in
agreement with those of another study
(Jarrett et al 1985), which used a
blood-sampling
ours.
source
of
method
discrepancy
inclusion in the present
identical with
to
results
of
Although
some
another
previous
potential
studies
study of four patients on benzodiazepines,
is
the
these
476
P.N.Sakkas etd
drugs
have
secretion
not
been
consistently
in non-depressed
found
individuals
to
substantially
influence
(Rubin et al 1973, Weitzman
1975, Bixler et al 1976, Shur et al 1983). Of course,
table
1
indicate
that
the
patients
taking
et al
it remains
shown whether this is also the case in depressed patients. on
GH
to be
Yet, the data
benzodiazepines
(I.D.:
1,4,5,6) had GH secretion values in the lower range. Moreover a little hours
the findings of the present study indicate that there was only overlap sleep
of
in the values between
specific disturbance depression
than
of GH secretion
depressed
1982, Kupfer
Nocturnal GH secretion
normal
tests
1984). However,
of subjects further confirmation
secretion
and
the
first
three
controls;
this
a better biological
other psychoendocrinological
Loosen and Prange,
GH
patients
could be potentially
during
marker
for
(Carroll et al 1981,
due to the small number
of these results is needed.
and slow wave sleep in depression
is most
prominent
during
the
first
2-3
hours
of
sleep
(Takahashi et al 1968, Honda et al 1969, Sassin et al 1969, Parker et al 1969,
Cauter
Van
predominates GH
et
in sleep
secretion
during
However, subsequent was
only
1992)
a
or
al
architecture. sleep
independently
is
research
facilitating
that
these
consistent
sleep-related decade
or
one
by
significant
GH secretion
a considerable
animals
and
demonstrated
in
time
(Karacan
to .SWS
(Mendlewicz are
et al
two
events
1985,
separate
period,
sws
thought
that
et
al
associated
1971).
Cauter
with
et al
which
sleep
are
onset,
as
during sleep, which did not demonstrate
relationship
of evidence,
human
Van
processes,
between
(Jarrett et al 1990b).
amount
normal
same
claimed that the role of SWS in GH secretion
phenomena
stimulated
the
it was initially
Thus,
related
evidenced by delta wave analysis a
During
1992).
controls
delta Yet,
accumulated
and
patients
activity
during
and
the last
from
research
with
depression,
in
that GHRH is the common stimulus of SWS and GH secretion and
that CRH acts as its counterpart
(Ehlers et al 1986, Holsboer et al 1988,
Obal et al 1988, Steiger et al 1922). Overall hormonal disturbances In
the
secretion of
sleep,
depressed
patients
and the amount these
two
in depression of
the
present
of SWS were decreased
parameters
were
not
found
study,
albeit
both
GH
during the first 3 hours to
be
correlated.
This
Growth hormone
depression.
abnormality
during
symptomatology
sleep. This
finding
is not significantly
different
al
1994).
1990a,
Thus,
decrease
of GH secretion
of major
depression
of
depression.
disturbances each
response
Non
may
suppression
of
to TRH and decreased
be
that
suggest
that
patients
cortisol
may
to
the
not
for nocturnal
In this context, depressed indication
of
disturbances; suitably
a
of
GHRH/CRH
the
fits
fact
this
serotoninergic
/ cholinergic
by serotoninergic
Finally, phase
half
may
interpreted
underlie
patients other
However,
imbalance
were
the DST
factors,
GH secretion
as
observed
such
as
a
because
is controlled
et al 1975) and
an
positives
may also be responsible,
(Reichlin 1981, Mendelson
our results of
appear
some
postulated
the propensity
that
been phase-advanced lights-out
Thus,
to be consistent
circadian
of
differ.
the
be
both
cholinergic
(Mendelson et al 1981).
advance
for
to
and reduced SWS found in the could
which
of
that sleep-related
pathophysiology
time
related
and do not need to go
in depression
study
imbalance
that theory.
there are indications
mechanisms
present
of the other two.
of depression.
GH hyposecretion
the
TSH
at least one of
disturbances
occur simultaneously
the blunted GH secretion
patients
with
blunted
during sleep were all present
biological
along with the clinical symptomatology
hormonal
correlated
dexamethazone,
that
Hypotheses
nocturnal
various
in each of our patients
the various
the
of the symptoms
be
did occur, more often independently
do not necessarily
state
is related to the pathophysiology
these abnormalities
depression,
intensity
that GH secretion
This
is indicative
the
of the GH secretion
reports
speculated
GH secretion
in only two cases. Nonetheless,
in
between
rather than to the intensity also
an
the acute and the remitted
in depression
results
constitute disturbance
(Steiger et al 1989, 1993; Jarrett
could
in depressed
present
other.
it
itself
These
between
depression
with
477
of sleep
and the disturbance
is consistent
in patients with endogenous et
secretion
GH
is independent
which
there was no correlation
Furthermore,
of the depressive
during sleep in depression
disturbed
that
indicates
finding
endocrinologic
secretion
depression
(Wehr
at the time
their
and
is
Goodwin
for sleep-related
in our patients, and
with
oscillators
GH
the hypothesis involved 1981).
It
secretion
in may may
that the be have
since both study groups had the same
sleep
our patients
latencies went
did
to bed,
not
significantly
their GH secretion
478
P.N. Sakkas et ul
responsiveness hypothesis
hypersecretion 1985,
may
have
to
some
is
in
Linkowski
already
depressed
et
al
studies are required
been
extent,
in
patients
1987,
1988).
to elucidate
decreased.
This
agreement
with
during
the
Whatever
day
the
GH
phase-advance
findings
of
(Mendlewicz
case,
more
the nature of this aberrant
GH
et
al
extensive pattern of
if there is indeed any.
GH secretion in depression,
Conclusions
The present
pronounced night
study of growth hormone
patients
depressed
and
reduction
to
normal
correlate with a positive same
GH
during sleep in ten male
normal
controls
controls.
This
finding
that
the
various
during
gives further
support
however
did
along
sleep,
with
the
reduction
in
indication
of
a
depression. central
of disturbed
Alternatively,
it
serotoninergic-cholinergic
nocturnal
could
of
CRH may
endocrine
represent
imbalance
in
SWS,
to the theory that GHRH is the common stimulus
play a major role in the pathophysiology during
not
to the
This disturbance
observed
SWS and GH release and that the ratio of GHRH and its counterpart
activity
a
neuroendocrinological
do not coexist in all depressed patients.
secretion
revealed
DST or TRH test which were administered
suggesting
subjects,
aberrations
secretion
matched
in GH secretion mainly during the first third of the
compared
as
eight
and/or
an a
circadian dysregulation.
Acknowledgements
This work was supported Foundation. Hatjitaskos,
Thanks
A. Koumoula,
the sleep laboratory
in part by Grant No F56-87 from the A.Onassis
are also
due to Drs C. Christodoulou,
and G. Sakellariou
A. Botsis,
P.
for their invaluable help in
data collection and the GH determinations.
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Inquiries and reprint requests should be addressed to:
Pavlos N. Sakkas, M.D., Department of Psychiatry Eginition Hospital 74 Vas. Sofias Ave, Athens 115 28 Greece
NeumPsyclmphwmanl.
& Bbl.
Psychht.
1996,
CopyrightQ
1998
Vol. 22.
pp. 467463
Elsevier SdenceInc.
Pdnted IntheUSA. Allrightsreserved 027%5646/96 PII
$19.00
+ .oO
t30275-5546(98)00019-9
GROWTH HORMONE SECRETION DURING SLEEP IN MALE DEPRESSED PATIENTS PAVLOS N. SAKKAS, CONSTANTIN R. SOLDATOS, JOANNE D. BERGIANNAKI, THOMAS J. PAPARRIGOPOULOS and COSTAS N. STEFANIS
Department
of Psychiatry, University of Athens, Greece.
( Final form. December
1997)
Abstract Sakkas, Pavlos N., Constantin R. Soldatos, Joanne D. Bergiannaki, Thomas J Paparrigopoulos and Costas N. Stefanis: Growth hormone secretion during sleep in male depressed patients. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1998, 22,pp.467-463.01998 ElsevierScienceInc. 1.
2. 3.
4.
Growth hormone (GH) secretion during sleep was studied in ten male patients with major depression according to DSM III and eight normal controls. Samples were collected through a continuous blood withdrawal pump while sleep was recorded in the laboratory. The results showed a marked decrease in the GH secretion mainly during the first three hours of sleep in depressed patients as compared to normal controls. DST and TRH tests were also administered to the same patients but no correlation was observed between a positive test and a blunted GH secretion, suggesting that the various neuroendocrinological disturbances do not coexist in all depressed patients. This disturbance in GH secretion during sleep, along with reduced slow wave sleep (SWS), gives support to the theory that GHRH is the common stimulus of SWS and GH release and that the ratio of GHRH and its counterpart CRH plays a major role in the pathophysiology of disturbed endocrine activity during sleep in depression.
Keywords: depression,
growth hormone, sleep, slow wave sleep.
Abbreviations: corticotropin releasing hormone (CRH), dexamethasone suppression test (DST), growth hormone (GH), growth hormone releasing hormone (GHRH), Hamilton depression rating scale (HDRS), luteinizing hormone releasing hormone (LHRH), rapid eye movements (REM), rapid eye movements latency (REM-L), slow wave sleep (SWS), thyrotropin releasing hormone (TRH), thyroid stimulating hormone (TSH).
467
P.N. Sakkas
et al
Introduction
Sleep is a powerful first two hours
physiologic
secreted in normal individuals GH secretion
stimulus
70-90s
of sleep,
with SWS
et al 1991, Van Cauter that no definitive SWS production
related
to the first non-REM period
et al 1992). Although
it was
in animals
et al 1988, Steiger
sleep
characteristic,
and in humans
albeit non-specific, mainly
and sleep architecture,
(Gillin 1983, Reynolds and Kupfer 1996).
patients
depressed
believed
(Sassin et al 1969, Karacan et al 1971) indicate
depressed
disturbances
patients
in their sleep
during the first 2-3 hours of
1987, Benca et al 1992; Soldatos
Furthermore, lower
show
that GHRH is the
(Ehlers et al 1986, Obal
et al 1992). On the other hand,
Paparrigopoulos
and
initially
answer could be given whether nocturnal GH release and
common stimulus of GH release and SWS production
efficiency
the
of GH is
(Takahashi et al 1968, Honda et al 1969, Ho11
are interdependent
more recent findings
manifest
during
24 hour amount
(Takahashi et al 1968). This sleep related
seems to be temporally
and particularly
for GH secretion;
of the total
it
is
responses
well
to
established
some
that
pharmacological
challenges of GH secretion as compared to normal controls
(Matussek et al
1980, Checkley et al 1981, Lesch et al 1987, Ansseau et al 1988, Laakmann et al 1990, Siever et al 1992, Holsboer 1995). Based
on
expectable GH
the
above,
depressed
patients
compared
to normal
in
rather
GH
in
secretion
depressed
pioneering
GH
peaks
secreted
hormonal
with
are
rather
secretion when
of
patients
(Schilkrut et al 1975). These
discrepant
results.
in depressed
during similar
sleep
few studies of
six were
findings were
studies of depressives both during the acute and 1993). Thus,
patients
Other in
was
sleep, amounts
when
secretion,
during the first 120-200 minutes
a
reduction
et al
during waking
patients
an overall
of sleep was found
diurnal
(Mendlewicz
in other reports
significant
however,
studies,
occurred
depressed
of GH despite
group. Nonetheless,
studies,
two
found
et al 1988). This hypersecretion
than
during
patients,
study,
nocturnal
(Steiger et al 1989,
of GH
SWS in the patient nocturnal
a
decreased
controls
state
1985, Linkowski
controls
showed
rather
hypersecretion
hours
In
in subsequent
the remitted resulted
sleep
results.
of
Yet, there have been relatively
during
secretion
contradictory
replicated
abnormalities
in depression.
and
reduction
focusing in
normal
GH
in
on the release
(Jarrett et al 1985,
Growth hormone secretion during sleep in depression
1990a,
Voderholzer
1994;
sample of depressed basal
nocturnal
(Rubin
et
pituitary
al
its overall
patients
GH
1993).
Our
in depressed
in
has
largest
showed no difference
responses
to
TRH
nocturnal
or
in
LHRH
secretion
(Stefanis et al 1985b).
on nocturnal
tests
of the
of
(Stefanis et al 1985a) as well as
profile
are presented.
other psychoendocrinological
GH
studied
depression
our findings
patients
or
group
in major
neuroendocrinological
present paper,
a study
Finally,
and normal controls
concentrations
1990).
hormones
et al
469
GH secretion
Also
In the
and sleep patterns
presented
are the
results
of
(DST and TRH) in the same individuals.
Methods
Subjects
Nocturnal
GH
secretion
patients
and
consents
were
patients
ranged between
22
59;
and
eight
obtained
the
significantly
was
normal
measured
controls.
before
they
during
All
sleep
subjects
entered
the
in
ten
were
depressed
male;
study.
The
informed
age
of
the
22 and 67, while that of normal controls between
mean
*SD
age
(40.9 + 14.1
of
the
for patients
two vs
groups
37.5
did
* 14.3
not
for
differ
controls).
Patients and controls were free of any physical
illness during the period
of
they
the
study,
and
endocrinological psychiatric drug
free
patients period; their
disorder.
history. for
their
at
Controls
Six patients
least
received
personal
15
small
days
fixed
history were
free
as well
as
before doses
IDS
Table
patients
Department Hospital
on
of
with
1) were
and
of
the diagnosis the
study
of
the
in
4) the
depression
(mean duration
weeks; mean number of previous
any
not past
normal the
report or
present
controls
study.
any
Only
during
were four this
(patients 1,5, and 6 as per
University
of major
did
benzodiazepines
(patient
hospitalised
Psychiatry
entering
one
of all
entering
three of them 1Omg of diazepam daily
depressed
before
in
3mg
of
bromazepam.
inpatient of
Athens
unit
of
The the
at
Eginition
for at least
two weeks
of present
episodes 1.7 f 1.4).
episode
5.1 f
1.2
P.N. Sal&as et a&
Assessments diagnosis
The
established
of
in all ten patients
10 as per their the
affective
major
criteria
IDS on Table of
1) by two independent (American
DSM-III
their depressive
Furthermore, item Hamilton
Depression
disorder-depressed
psychiatrists
Psychiatric
symptomatology
Rating Scale
Association
was evaluated
was 5 and using
1980).
using the 21-
(HDRS) (Hamilton 1960); only those
who scored above 22 were included in the study 32.2 + 9.16). These patients
episode
(two with bipolar illness, patients
(their mean score rt SD was
had no other current diagnoses
on axis I of
the DSM III. Three
to seven
DST following
days before
the sleep
standard procedures
study,
all patients
underwent
a
(Carroll et al 1981). Eight of them had
also a TRH test on the day before the DST; they were injected with 400pg of synthetic min
after
TRH and their TSH response was measured
the
increase of plasma
test
was
to its baseline value
the TRH
evaluated
30, 60, 90, and 120 as
blunted
when
the
level of TSH after the infusion of TRH, was less than
6uU/ml as compared patients
This
injection.
test was
(Loosen and Prange 1982). In two
not completed
for technical
reasons.
None
of
the controls had a DST or TRH test during the study. The sampling while
of GH secretion recorded
were
subjects
technique
(Rechtschaffen
instructed
to
wakefulness
and
potentially adaptation not
diet
psychoactive night before
considered
to
be
shown to be practically 1967, Sakkas
using Kales
All
previous
and
substances. the actual
necessary,
lights through
were
turned
polysomnographic our
to the
abstain
from
subjects
study,
For both study
because
alcohol groups
adaptation
were
a sleepthe night
to have a regular and
other
there was no
study night. An adaptation
absent in depressed patients
One to three hours before
laboratory
to that of the day preceding
schedule
1974, Browman and Cartwright
connected
of
Further, they were instructed
et al 1990) as well as in normal
p.m. when
in the sieep
standard
the
1968).
the week
comparable
spent in the laboratory. rest-activity
and
during
follow,
schedule
was accomplished
effects
night was have
been
(Mendels and Hawkins
individuals
(Coble et al
1980). an E-hour sleep recording off to about
a nonthrombogenic
6.30 a.m.)
(from about 10.30 every
subject
was
cannula and a long blood catheter to
Growth hormone secretion during sleep in depression an ambulatory test tube adjacent
continuous
withdrawal
pump
471
the blood
leading
sample
(Kowarski et al 1971). Using this pump, which was located in an room
the authors
were
able without
take hourly blood samples throughout
disturbing
the
the night by changing
subjects
hour
of
each
blood
which
fluctuations
sample have
may
collection
controlling
since
occurred
collection. All blood samples were immediately was
frozen
at
radioimmunoassay the evaluation l
since
-25C"
the hormonal
were
GH
sample
and the plasma
determined
using
of this method was 0.3ng/ml.
Baseline value of GH level. As such, the authors considered during the 1-3 hour period before
of the sleep recording. to
any
a
For
of GH secretion we used the following measures:
value of GH secretion
tried
during the
for
previous
centrifuged
levels
the sensitivity
method;
the
to
the test tube
every hour. Thus, the mean GH secretory rate could be measured whole
to a
avoid
By choosing
as much
the lowest pre-sleep
as possible
the
effect
on GH
the lowest
the beginning GH value, we levels
of
the
stress related to the cannulation procedure. l
Maximal
GH
level
sleep,
during
as
it
was
determined
in
the
blood
samples after sleep onset. l
Total GH secretion during sleep time, represented plasma
GH
curve.
We
estimated
this
area
by
as the area under the
multiplying
the
GH
mean
value of each hour by the minutes spent asleep after sleep onset during this hour of the night. l
GH
secretion
during
estimated measuring
the
first
three
hours
of
sleep,
which
was
also
the area under the plasma GH curve that corresponds
to the first three hours after sleep onset. Polysomnographic standardized
data
procedures
objective assessment and
SWS
was
established 1, having
were
scored
of wakefulness
obtained
for
each
with the appearance a duration
using
(Rechtschaffen
30
and
set
Kales
epochs 1968).
based
on
Thus,
an
as well as REM and sleep stages 1, 2,
subject
night.
The
onset
of
sleep
was
of any stage of sleep, other than stage
of one minute
or greater.
sleep was stage 1, it had to be followed without
If the initial any intervening
stage of wake by
at least one minute of either stage 2,3,4 or REM. REM latency was defined in
terms
of
minutes
elapsed
from
sleep
onset
occurrence of the first REM epoch, subtracting wakefulness.
to
REM
onset
i.e.
the
the minutes of intervening
472
P.N. Sakkas et cd_
Data Analysis
The data were
analyzed
using
Student's
t-test
and
Pearson's
product-
moment correlation.
GH nglml 0\1=8)
_T. I
( ’ (N=S)
(N=8}
6-
T’
/T,
- 5-
/
I--
l0
I 1
I 2
I 4
I 3
I‘
I 5
-
T-@ I
6
7
8
Time lapsed from Sleep Onset (hours) and normal Fig 1. GH secretion curves of depressed patients (_) controls (---) during nocturnal sleep. Each curve depicts the mean hourly GH levels + SD.
Results Overall GH secretory patterns Figure 1 shows the overall and normal controls the
sleep
pattern
onset.
There
of the two
increased
secretion
was
study of
GH
secretion
during
the
a
clear-cut
groups. during
whereas the depressed patients GH
GH secretory
pattern
of depressed
during the night. The reference
same
Normal the
point
difference controls
first
3-4
of
sleep.
the
manifested hours
showed a less pronounced hours
in
GH
of
patients
(0) represents secretory a markedly
their
sleep,
increase in their
secretion
and
sleep
Growth hormone secretion during sleep in depression
parameters
patients
depressed
of
individually
and
473
controls
normal
shown
are
on Table 1 and in terms of mean values on Table 2.
Table 1
GH Secretion and Other Sleep and Psychoendocrinological Parameters of Depressed Patients and of Normal Controls.
I.D.
REM-L"
GH/3ha
Age
DST
SWS/3h"
TRH
HDRS
Depressed patients 1 2 3 4 5 6 7 8 9 10
43 67 45 49 22 42 25 23 42 51
44 162 234 258 267 336 341 644 1170 1380
19 49 15 21 81 48 59 186 126 44
0 0 0 0 6 12 34 11 4 2
+
41 26 24 24 30 22 21 38 43 41
+ + +
+ t
+ + t
Normal controls 50 32 32 26 22 59 26 53
1
2 3 4 5 6 7 8
240 618 732 842 948 1255 1380 2124
14 37 51 64 72 12 14 21
100
15 91
66 58 64 85 81
'GH/3h: GH secretion during the first 3 hours of sleep (min ng/mg); L'~~~L: REM latency (min); 'SWS/3h: SWS during the first 3 hours of sleep (min)
As Table 2 shows, there was no significant baseline and highest two groups. lower
total
(p
GH
However, amount
there was a trend for depressed of
Furthermore, during
growth the
hormone
difference
secretion between
in terms of both
during
the
as presented
first
three
patients
during
patients
the first three hours of sleep
secretion
individually,
difference
sleep levels of growth hormone secretion between the
and
in Table 1, relatively
of
sleep
sleep
controls
(pcO.05). When
hours
to have a
nocturnal
was
the values
were
observed
little overlap of these
P.N.Sal&as etal.
474
values between
the two groups was found. Only one normal control's value
was below a cut-off values
patients' diagnostic
point
of 500 min x ng/ml while just three depressed
exceeded of
sensitivity
it.
Consequently,
this
based
measurement
is
on
this
70YJ and
its
sample
the
specificity
81.5%. Table 2
Sleep Patterns and GH Secretion: Depressed Patients vs Controls
Depressed
Controls
10
8 37.5 rt 14.3
N
Age
40.9 f 14.1
t-test
Sleep Characteristics" Total sleep time Total REM time REM latency Total SWS time SWS time/3h
261.6 rt 103 52.9 k 23.2 65.4 f 41.1 17.0 + 26.4 6.9 k 10.6
304.5 62.0 78.2 61.7 43.9
k + + + k
NS
14,6 28.3 27.5 27.2 25.0
NS NS
PC.01 PC.01
GH secretion parameters Baseline levelb Highest sleep levelb Total sleep secret.' Secret./first 3hrs' "Time in minutes;
Sleep patterns In
terms
difference time, total
no
as
depressed REM
well
as
between
rate during
the
of
and
data analysis
correlation amount
polysomnographic
0.7 9.4 1469.2 1017.3
NS
!L 0.2 _+ 5.6 f 663.0 + 572.4
for
between wave
there
NS
PC.1 p<.o5
in min x ng/ml
and controls (Table 2).
the
first
was
no
significant
regarding
total sleep
Slow
three
wave
hours
within
the depressed
amount
of
group,
age
and
sleep
slow
there growth
sleep of
wave
was
no
hormone
(r=-0.61)
during
for
sleep
group that in the controls.
the was
However,
group showed that there is sleep
and
the three first hours of sleep
depressed
slow
data,
patients latency
less in the depressed
correlation
secretion within
the
between
individual
0.3 4.5 631.0 437.0
bGH values in ng/ml; 'The GH secretion
REM minutes night
* + k f
& GH secretion
of
significantly
0.5 6.0 915.9 487.0
growth
statistically secretion the
hormone
(r=0.03). Moreover,
first
rate
significant (r=0.02) or
three
hours
of
Growth hormone secretion during sleep in depression
the
sleep;
correlation,
latter
sample,
is
quite
strong.
between
the amount
non-significant
albeit
Furthermore,
or the percentage
no
475
for
correlation
could
of any particular
sleep
our
small
be
found
stage and
the GH secretory activity at any period of sleep. Other neuroendocrinological
tests
Seven out of ten patients
had an abnormal
the two psychoendocrinological not adequately
sleep and response
depressive
TSH response
between
no correlation
response
in at least one of
(Table 1). Dexamethasone
could
suppress cortisol secretion in five patients while four of
them had a blunted correlation
tests used
GH
to TRH. As Table
hyposecretion
during
the
1 shows, there was no first
three
hours
of
in either the DST or the TRH test. Finally, there was
between
any value of the GH secretion and severity of the
symptomatology
as measured
by
the
either
HDRS,
in terms
item scores. Even the strongest
total score or of individual
of
correlation
(r=0.5) which was found between GH secretion during the first three hours of sleep and total HDRS score was not statistically
significant
evidently
due to the small sample size.
Discussion Nocturnal GH secretion in depression The most notable result of the present study is the clear-cut in
GH
nocturnal
secretion
in
depressed
patients
compared
decrease
with
normal
controls, mainly during the first part of the night. Previous studies had shown that nocturnal
GH secretion
et al 1975, Steiger
et al 1989, 1993; Jarrett
Voderholzer
in depressives
et al 1993), or similar
may be lower
et al 1985,
(Schilkrut
1990a,
1994;
(Mendlewicz et al 1985, Linkowski
et
al 1988; Rubin et al 1990) to that of normal controls. Of these studies, in only one a large sample was employed
(Rubin et al 1990). However,
in
that study, which is at variance with ours, both male and female subjects were
included
utilized.
and
On the
a
other
blood-sampling hand,
method
different
it is noteworthy
that
our
than
ours
results
was
are
in
agreement with those of another study
(Jarrett et al 1985), which used a
blood-sampling
ours.
source
of
method
discrepancy
inclusion in the present
identical with
to
results
of
Although
some
another
previous
potential
studies
study of four patients on benzodiazepines,
is
the
these
476
P.N.Sakkas etd
drugs
have
secretion
not
been
consistently
in non-depressed
found
individuals
to
substantially
influence
(Rubin et al 1973, Weitzman
1975, Bixler et al 1976, Shur et al 1983). Of course,
table
1
indicate
that
the
patients
taking
et al
it remains
shown whether this is also the case in depressed patients. on
GH
to be
Yet, the data
benzodiazepines
(I.D.:
1,4,5,6) had GH secretion values in the lower range. Moreover a little hours
the findings of the present study indicate that there was only overlap sleep
of
in the values between
specific disturbance depression
than
of GH secretion
depressed
1982, Kupfer
Nocturnal GH secretion
normal
tests
1984). However,
of subjects further confirmation
secretion
and
the
first
three
controls;
this
a better biological
other psychoendocrinological
Loosen and Prange,
GH
patients
could be potentially
during
marker
for
(Carroll et al 1981,
due to the small number
of these results is needed.
and slow wave sleep in depression
is most
prominent
during
the
first
2-3
hours
of
sleep
(Takahashi et al 1968, Honda et al 1969, Sassin et al 1969, Parker et al 1969,
Cauter
Van
predominates GH
et
in sleep
secretion
during
However, subsequent was
only
1992)
a
or
al
architecture. sleep
independently
is
research
facilitating
that
these
consistent
sleep-related decade
or
one
by
significant
GH secretion
a considerable
animals
and
demonstrated
in
time
(Karacan
to .SWS
(Mendlewicz are
et al
two
events
1985,
separate
period,
sws
thought
that
et
al
associated
1971).
Cauter
with
et al
which
sleep
are
onset,
as
during sleep, which did not demonstrate
relationship
of evidence,
human
Van
processes,
between
(Jarrett et al 1990b).
amount
normal
same
claimed that the role of SWS in GH secretion
phenomena
stimulated
the
it was initially
Thus,
related
evidenced by delta wave analysis a
During
1992).
controls
delta Yet,
accumulated
and
patients
activity
during
and
the last
from
research
with
depression,
in
that GHRH is the common stimulus of SWS and GH secretion and
that CRH acts as its counterpart
(Ehlers et al 1986, Holsboer et al 1988,
Obal et al 1988, Steiger et al 1922). Overall hormonal disturbances In
the
secretion of
sleep,
depressed
patients
and the amount these
two
in depression of
the
present
of SWS were decreased
parameters
were
not
found
study,
albeit
both
GH
during the first 3 hours to
be
correlated.
This
Growth hormone
depression.
abnormality
during
symptomatology
sleep. This
finding
is not significantly
different
al
1994).
1990a,
Thus,
decrease
of GH secretion
of major
depression
of
depression.
disturbances each
response
Non
may
suppression
of
to TRH and decreased
be
that
suggest
that
patients
cortisol
may
to
the
not
for nocturnal
In this context, depressed indication
of
disturbances; suitably
a
of
GHRH/CRH
the
fits
fact
this
serotoninergic
/ cholinergic
by serotoninergic
Finally, phase
half
may
interpreted
underlie
patients other
However,
imbalance
were
the DST
factors,
GH secretion
as
observed
such
as
a
because
is controlled
et al 1975) and
an
positives
may also be responsible,
(Reichlin 1981, Mendelson
our results of
appear
some
postulated
the propensity
that
been phase-advanced lights-out
Thus,
to be consistent
circadian
of
differ.
the
be
both
cholinergic
(Mendelson et al 1981).
advance
for
to
and reduced SWS found in the could
which
of
that sleep-related
pathophysiology
time
related
and do not need to go
in depression
study
imbalance
that theory.
there are indications
mechanisms
present
of the other two.
of depression.
GH hyposecretion
the
TSH
at least one of
disturbances
occur simultaneously
the blunted GH secretion
patients
with
blunted
during sleep were all present
biological
along with the clinical symptomatology
hormonal
correlated
dexamethazone,
that
Hypotheses
nocturnal
various
in each of our patients
the various
the
of the symptoms
be
did occur, more often independently
do not necessarily
state
is related to the pathophysiology
these abnormalities
depression,
intensity
that GH secretion
This
is indicative
the
of the GH secretion
reports
speculated
GH secretion
in only two cases. Nonetheless,
in
between
rather than to the intensity also
an
the acute and the remitted
in depression
results
constitute disturbance
(Steiger et al 1989, 1993; Jarrett
could
in depressed
present
other.
it
itself
These
between
depression
with
477
of sleep
and the disturbance
is consistent
in patients with endogenous et
secretion
GH
is independent
which
there was no correlation
Furthermore,
of the depressive
during sleep in depression
disturbed
that
indicates
finding
endocrinologic
secretion
depression
(Wehr
at the time
their
and
is
Goodwin
for sleep-related
in our patients, and
with
oscillators
GH
the hypothesis involved 1981).
It
secretion
in may may
that the be have
since both study groups had the same
sleep
our patients
latencies went
did
to bed,
not
significantly
their GH secretion
478
P.N. Sakkas et ul
responsiveness hypothesis
hypersecretion 1985,
may
have
to
some
is
in
Linkowski
already
depressed
et
al
studies are required
been
extent,
in
patients
1987,
1988).
to elucidate
decreased.
This
agreement
with
during
the
Whatever
day
the
GH
phase-advance
findings
of
(Mendlewicz
case,
more
the nature of this aberrant
GH
et
al
extensive pattern of
if there is indeed any.
GH secretion in depression,
Conclusions
The present
pronounced night
study of growth hormone
patients
depressed
and
reduction
to
normal
correlate with a positive same
GH
during sleep in ten male
normal
controls
controls.
This
finding
that
the
various
during
gives further
support
however
did
along
sleep,
with
the
reduction
in
indication
of
a
depression. central
of disturbed
Alternatively,
it
serotoninergic-cholinergic
nocturnal
could
of
CRH may
endocrine
represent
imbalance
in
SWS,
to the theory that GHRH is the common stimulus
play a major role in the pathophysiology during
not
to the
This disturbance
observed
SWS and GH release and that the ratio of GHRH and its counterpart
activity
a
neuroendocrinological
do not coexist in all depressed patients.
secretion
revealed
DST or TRH test which were administered
suggesting
subjects,
aberrations
secretion
matched
in GH secretion mainly during the first third of the
compared
as
eight
and/or
an a
circadian dysregulation.
Acknowledgements
This work was supported Foundation. Hatjitaskos,
Thanks
A. Koumoula,
the sleep laboratory
in part by Grant No F56-87 from the A.Onassis
are also
due to Drs C. Christodoulou,
and G. Sakellariou
A. Botsis,
P.
for their invaluable help in
data collection and the GH determinations.
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Inquiries and reprint requests should be addressed to:
Pavlos N. Sakkas, M.D., Department of Psychiatry Eginition Hospital 74 Vas. Sofias Ave, Athens 115 28 Greece