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The Journal of International Medical Research
2003; 31: 36 – 41
36
Natural-killer-(NK)-cell activity and blood
levels of interleukin 2 (IL-2), dehydro-
epiandrosterone (DHEA), DHEA sulphate
(DHEA-S) and cortisol were measured in
17 patients with major depression and
10 control subjects. Depression severity
was evaluated using the Zung Self-rating
Depression Scale. NK-cell activity and IL-2
levels were measured using a chromium-
51 release test and an enzyme-linked
immunosorbent assay, respectively. Radio-
immunoassays were used to measure
serum cortisol, DHEA and DHEA-S. As
would be expected, patients with major
depression had a higher score on the Zung
Self-rating Depression Scale than healthy
controls. Compared with controls, NK-cell
activity and levels of cortisol and DHEA
were reduced in patients with major
depression, whereas IL-2 levels were
increased. No difference was observed in
DHEA-S levels between patients and
controls. A reduction in NK-cell activity
and DHEA levels, and an increase in IL-2
levels appear to be associated with major
depression. Whether these changes are the
cause or the consequence of the depression
remains to be determined.
KEY WORDS: MAJOR DEPRESSION; NATURAL-KILLER-CELL ACTIVITY; INTERLEUKIN 2;
DEHYDROEPIANDROSTERONE; CORTISOL
Introduction
Changes in immunological parameters have
been demonstrated in mental diseases by
Jozuka,1 – 5 Masek et al.6and Webster et al.,7
and there is evidence of a bidirectional
relationship between the brain and the
immune system.8The presence of various
indicators of immune activation has been
demonstrated in depressed patients,9 – 11 and
such patients display an increased number
of T cells in an early phase of activation.12
Major depression has also been shown to be
accompanied by decreased serum activity of
dipeptidyl peptidase IV, a membrane-bound
serine protease that catalyses the cleavage of
various cytokines and neuroactive peptides,
stimulating T-cell activation and the
production of cytokines such as interleukin 2
(IL-2).13 Various direct and indirect indicators
Comparison of Immunological and
Endocrinological Markers Associated
with Major Depression*
H JOZUKA1, E JOZUKA1, S TAKEUCHI2AND O NISHIKAZE3
1Department of Psychiatry and Psychosomatic Medicine, Jozuka Mental Clinic and JMC
Stress Medical Institute, Aichi, Japan; 2Department of Clinical Laboratory Medicine, Handa
Health Control Centre in co-operation with Health Association, Aichi, Japan; 3Department
of Clinical Laboratory Medicine, Hokkaido University, Hokkaido, Japan
*This study was presented at the 40th Congress of
Psychosomatic Medicine, Aomori, Japan, 1999.
of a moderate activation of the inflam-
matory response system, particularly an
increased production of proinflammatory
cytokines,14 have also been reported.
Jozuka2 – 5 has suggested that reduced
activity of the body’s initial defence system,
including the innate immune response
as represented by natural-killer-(NK)-cell
activity, and increased activity of the body’s
secondary defence system or cellular
immunity, represented by T-cell activity, are
characteristic immunological changes in
major depression.
Dehydroepiandrosterone (DHEA) is pro-
duced in the brain and adrenal cortex and
is thought to be involved in cellular repair
and recovery.15 – 17 Specifically, it is thought
to maintain nerve-cell function in brain
tissue and promote immune function in
peripheral tissue.16 It has been suggested
that low levels of DHEA in the morning may
be associated with major depression, at least
in adolescents.18
The aim of the present study was to
compare NK-cell activity (as an indicator of
the body’s initial defence system), IL-2 levels
(as indicators of cellular immunity) and
endocrine mechanisms (in particular
measurements of serum cortisol, DHEA and
DHEA sulphate [DHEA-S]) in patients with
major depression with those in controls.
Patients and methods
PATIENTS
The study, first presented at the 40th
Congress of Psychosomatic Medicine,
Aomori, Japan, 1999, was approved by the
local ethics committee and involved patients
diagnosed with major depression according
to the DSM-III-R criteria at the Jozuka
Mental Clinic, Aichi, Japan, in the period
from October 1994 to September 1998.
Patients were selected on the basis of a first
depressive episode. They had received no
treatment at the time the blood samples
were taken, and they were all free of allergic
or infectious reactions for at least
2 weeks prior to blood collection. The aim of
the study was explained, and informed
consent to participate was obtained from
each patient. The control group consisted of
welfare volunteers and clinic staff with no
history of mental disorders. The age and
weight of the patients and controls were
recorded.
EXPERIMENTAL PROCEDURES
Blood was collected between 09.00 and
10.00. Within 24 h, NK-cell activity was
measured with a chromium-51 (51Cr) release
test using Na2
51CrO4.19,20 Levels of IL-2 were
measured with a commercial enzyme-linked
immunosorbent assay (ELISA) kit by a tube-
fixation method that uses several
monoclonal antibodies that identify different
epitopes of human IL-2 within a range of
50 – 1600 pg/ml. Cortisol, DHEA and
DHEA-S levels were determined using radio-
immunoassays.21
The Zung Self-rating Depression Scale
(SDS)22 was used to evaluate the severity of
depressive symptoms in both patients and
controls.
STATISTICAL ANALYSIS
Results were analysed using the Student’s
t-test with significance taken as P < 0.05.
Results
A total of 17 patients (nine women and eight
men) were included in the study. Their ages
ranged from 23 to 54 years (mean ± SD,
40.3 ± 15.1 years) and their weights from
41 to 74 kg (mean ± SD, 58.6 ± 6.2 kg). The
control group consisted of 10 people (six
women and four men) with ages ranging
from 23 to 51 years (mean ± SD, 39.9 ±
9.8 years) and weights ranging from 39 to
37
H Jozuka, E Jozuka, S Takeuchi et al.
Comparison of immunological and endocrinological markers in depression
TABLE 1:
Measured parameters in controls and in patients with major depression
Controls (n= 10) Depressed patients (n= 17)
Natural-killer-cell activity (%) 26.4 ± 17.3 7.5 ± 2.5b
Interleukin 2 (pg/ml) 344 ± 98 542 ± 111b
Cortisol (µg/dl) 12.3 ± 3.8 7.1 ± 4.5a
DHEA (mg/ml) 5.6 ± 1.5 3.3 ± 0.8b
DHEA-sulphate (mg/ml) 1116 ± 452 1621 ± 818
SDS score 32 ± 7 55 ± 3b
Values are mean ± SD.
aP< 0.05 and bP< 0.01 compared with controls.
DHEA, dehydroepiandrosterone; SDS, Zung Self-rating Depression Scale.
70 kg (mean ± SD, 54.2 ± 8.9 kg). There was
no difference between the two groups for
either age or weight.
The levels of the various parameters
measured in patients and controls are given
in Table 1. As would be expected, patients
with major depression had significantly
higher SDS scores than controls (P< 0.01).
The NK-cell activity was significantly lower
(P< 0.01) and IL-2 levels were significantly
higher (P< 0.01) in patients with major
depression compared with controls. Cortisol
and DHEA levels were significantly lower in
depressed patients than in controls (P< 0.05
and P< 0.01, respectively). No significant
difference was observed in DHEA-S levels
between patients and controls.
Discussion
In the present study, NK-cell activity and
IL-2 levels were measured as indicators of
immune activity, and serum cortisol, DHEA
and DHEA-S were measured as indicators of
endocrine function.
The reduction in NK-cell activity found
in patients with major depression is in agree-
ment with earlier observations.23 – 25 The
enhancement of IL-2 in depressed patients
may be a compensatory response to the
reduced NK-cell activity.26,27 As discussed
by Carson et al.,28 it would be very
dangerous for a living organism not to
compensate for decreased first-line defence
(i.e. NK-cell activity).
The fundamental question remains,
however, as to whether depression causes
these immunological and endocrinological
changes or whether they are themselves the
cause of the depression. There is some
evidence to suggest that treatment with IL-2
and interferon-αcan induce depressive
symptoms and activation of the inflam-
matory response system.29 Anti-depressants
have negative immunoregulatory effects
both in vitro and in vivo, and their anti-
depressant efficacy may, at least in part, be
related to their immunological effects.14
Hyperactivity of the hypothalamic–
pituitary–adrenal axis and raised cortisol
levels are well documented in depression.30,31
Miller et al.32 have reported raised serum
cortisol levels in major depression. The
reason for the discrepancy between these
results and those found in this study is not
clear. Cortisol levels vary considerably
depending on the time of blood collection,
the mental state of the person and the period
of time after the onset of major depression,2
and thus are probably the least reliable
markers of those measured in this study.
38
H Jozuka, E Jozuka, S Takeuchi et al.
Comparison of immunological and endocrinological markers in depression
39
H Jozuka, E Jozuka, S Takeuchi et al.
Comparison of immunological and endocrinological markers in depression
Dehydroepiandrosterone promotes the
synthesis of IL-2 and interferon-γ, and inhibits
the suppression of IL-2 and interferon-γ
synthesis by glucocorticoids.
33
Nishikaze and
Furuya
16
have suggested that DHEA, via its
antagonism of glucocorticoids, acts as an anti-
stress agent that facilitates tissue recovery.
15,34
There is also evidence to suggest that DHEA acts
to cause tumour regression.
33
In the field of
psychiatry, Goodyer et al.
18
have suggested that
low DHEA levels in the morning may be
associated with major depression, at least in
adolescents, and when patients suffering from
major depression were treated with DHEA,
improvements were observed in their depressive
symptoms.
35
It is not known whether the
decrease in DHEA seen in depressed patients is a
cause or a consequence of their depression.
Levels of DHEA-S are much higher than
those of DHEA, and thus it is difficult
to observe changes of the order of those
seen with DHEA. DHEA-S levels are only
thought to change substantially just before
death, however, when there is a large
decrease.
15
It seems reasonable to postulate that there
may be a link between the decreases in NK-cell
activity and DHEA levels and the increase in
IL-2 found in patients with major depression,
but the question of cause or consequence is
pertinent. Since depressed mood has been
shown to be associated with reduced NK-cell
activity, some investigators have studied the
effect of anti-depressants on this parameter.
Serotonin, which is thought to be implicated in
the pathophysiology of affective disorders,
enhances NK-cell activity in vitro and
lymphocytes possess serotonin transporters and
receptors.
36
NK-cell activity was evaluated in
depressed patients before and after treatment
with the selective serotonin reuptake inhibitor
(SSRI) fluoxetine, and the possible direct effects
of this SSRI on NK-cell activity with lymphoid
cells in vitro were studied.
36
Fluoxetine was
found to enhance NK-cell activity not only in
vivo (in patients, with amelioration of their
depressive symptoms) but also in vitro. The latter
observation suggests a possible direct drug
interaction with lymphocytes. Helgason et al.
37
found similar results in vitro using paroxetine
and norfluoxetine.
The present study involved a small number
of patients and the results need to be verified in
a larger number of patients and controls,
preferably with repeated measurements of the
various parameters. Although the question of
cause or consequence remains unanswered, this
work is compatible with a possible immuno-
logical and endocrinological contribution to the
cause of the depressive state. In the light of this,
pharmacological treatment of depression may
result in enhanced immune competence as
indicated by increased NK-cell activity. If,
indeed, anti-depressant drugs are capable of
enhancing immune competence, their use
would appear to be justified in individuals with
compromised immune function, such as those
with cancer.
Acknowledgement
The authors express their deepest
appreciation to the many patients who
co-operated in the present study.
• Received for publication 4 October 2002 • Accepted 15 October 2002
Copyright © 2003 Cambridge Medical Publications
40
H Jozuka, E Jozuka, S Takeuchi et al.
Comparison of immunological and endocrinological markers in depression
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Address for correspondence
Dr H Jozuka
Department of Psychiatry and Psychosomatic Medicine, Jozuka Mental Clinic and
JMC Stress Medical Institute, 1-18 Hananokicho, Nishio, Aichi, Japan.
E-mail: hjozuka@aichi.med.or.jp