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Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 679 685

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Stress at work alters serum brain-derived neurotrophic factor (BDNF) levels

and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in
healthy volunteers: BDNF and MHPG as possible biological
markers of mental stress?
Masae Mitoma, Reiji Yoshimura , Atsuko Sugita, Wakako Umene, Hikaru Hori,
Hideki Nakano, Nobuhisa Ueda, Jun Nakamura
Department of Psychiatry, University of Occupational and Environmental Health, Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 8078555, Japan
Received 27 August 2007; received in revised form 9 November 2007; accepted 9 November 2007
Available online 17 November 2007

Abstract
There is growing evidence that blood levels of brain-derived neurotrophic factor (BDNF) and catecholamine, and cytokines are related to not
only to depressive, suicidal, and anxious states but also to depression-associated personality traits. Psychological job stress is well known to lead
to symptoms of depression and anxiety. In the present study, we examined effects of psychological job stress on serum levels of BDNF and plasma
levels of catecholamine metabolites, and cytokines in healthy volunteers (n = 106, male/female = 42/64, age = 36 12 yr) working in a hospital
setting. The values (mean SD) of scores for stress items in the Stress and Arousal Check List (s-SACL), plasma MHPG levels, and, serum BDNF
levels in all participants were 7.2 3.3, 5.2 3.4 ng/mL, and 23.3 14.7 ng/mL, respectively. A negative correlation was found between scores for
s-SACL and serum BDNF levels (rho = 0.211, p = 0.022). A positive correlation was also found between scores on the s-SACL and plasma levels
of 3-methoxy-4-hydroxyphenylglycol (MHPG) (rho = 0.416, p = 0.01), but not homovanillic acid (HVA). No relationship was found between sSACL scores and plasma levels of interleukin-6 (IL-6) or tumor necrosis factor (TNF). These results suggest that serum BDNF levels and
plasma MHPG levels might be biological markers reflective of psychological job stress in hospital employees.
2007 Published by Elsevier Inc.
Keywords: BDNF; Biological marker; HVA; MHPG; Psychological job stress

1. Introduction
Depressed patients exhibit pathological changes in particular
brain areas, including the limbic (hippocampus and amygdale)
and cortical brain regions (Bremner et al., 2000; Mervaala et al.,
2000; Manji et al., 2001; Drevetz et al., 1997). Brain-imaging
studies of depressed patients indicate impairments in blood flow
and decreases in the volume of cortical and limbic structures
(Drevetz, 2001; Mervaala et al., 2000). One major neurotrophic
factor, brain-derived neurotrophic factor (BDNF), has been
Abbreviations: BDNF, brain-derived neurotrophic factor; MHPG, 3methoxy-4-hydroxyphenylglycol; HVA, homovanillic acid; IL-6, interleukin6; TNF, tumor neurosis factor ; SACL, stress and arousal check list.
Corresponding author. Tel.: +81 936917253; fax: +81 936924894.
E-mail address: yoshi621@med.uoeh-u.ac.jp (R. Yoshimura).
0278-5846/$ - see front matter 2007 Published by Elsevier Inc.
doi:10.1016/j.pnpbp.2007.11.011

found to play a critical role in long-term potentiation, a cellular

mechanism of learning and memory, suggesting that this
neurotrophic factor can influence neuroplasticity (Figurov
et al., 1996; Korte et al., 1995). BDNF is also needed for the
survival and guidance of neurons during development and for the
survival and function of neurons during adulthood (Duman et al.,
2000; McAllister et al., 1999; Thoenen, 1995). The atrophy and
loss of hippocampal or cerebral cortical neurons and/or glia could
result from a stress-induced loss of neurotrophic factors, from
other processes that compromise neuronal function and activity
or other insults, as a result of the patient's genetic background
(Sapolsky, 2000; Shelton, 2000). BDNF has been studied widely
in stress conditions and may play a crucial role in depression and
anxiety in animal models (Duman et al., 1997; Duman and
Monteggia, 2006). The source of circulating BDNF remains
unknown. Platelets, brain neurons, and vascular endothelial cells

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M. Mitoma et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 679685

are currently considered to be putative sources. It was

demonstrated that BDNF crosses the bloodbrain barrier (Pan
et al., 1998) and that BDNF levels in the brain and serum have
been shown to undergo similar changes during the maturation and
aging process in rats (Karege et al., 2002a). Furthermore, Lang
et al. (in press) recently reported that serum BDNF concentrations
reflect some aspects of neuronal plasticity, as indicated by the
association of BDNF levels with those of N-acetylaspartate level
in the cerebral cortex. These results indicated that blood BDNF
levels might in part reflect the BDNF levels in the brain. Several
studies have demonstrated that decreased blood levels of BDNF
in patients with depression (Karege et al., 2002b; Shimizu et al.,
2003; Gonul et al., 2005; Yukimasa et al., 2006; Yoshimura et al.,
2007a,b), suicidal behavior (Kim et al., 2007), schizophrenia
(Shoval and Weizman, 2005), and anxiety disorders (Kobayashi
et al., 2005). In addition, Lang et al. (2004) reported observing
decreased serum BDNF levels in healthy volunteers with
neuroticism, a depression-related personality trait. The authors
also reported that an association was found between the BDNF
gene Val66Met polymorphism and anxiety-related personality
traits (Lang et al., 2005). On the contrary, Surtees et al. (2007) did
not find any evidences to support an association between the
BDNF gene Val66Met polymorphism and mood status in a large
non-clinical sample. Thus, it remains controversial whether or not
BDNF is involved in the etiology of mood- or stress-related
phenotypes.
On the other hand, the plasma levels of 3-methoxy-4hydroxyphenylglycol (MHPG), a major metabolite of noradrenaline, and homovanillic acid (HVA), a major metabolite of
dopamine, are reported to reflect noradrenergic and dopaminergic
neuronal tone, respectively in humans (Kopin, 1985). A number
of studies have suggested that plasma levels of MHPG and HVA
parallel concentrations in the brain and cerebrospinal fluid
(Nagaoka et al., 1997; Yoshimura et al., 2004). Previously, we
reported that plasma MHPG levels correlated with the severity of
anxiety in depressed patients (Ueda et al., 2002; Shinkai et al.,
2004; Yukimasa et al., 2006). Taken together, the findings thus far
suggest that blood levels of BDNF and MHPG may serve as
biomarkers of stress-related symptoms such as depression and
anxiety. In addition, Fukuda et al. (1996) have demonstrated that a
significant positive correlation was found between plasma
MHPG, but not HVA, and psychological stress in healthy
volunteers. Mizuki et al. (1992) have reported that a increase of
dopamine turnover (HVA/DA) was observed by the addition of
mental task in the normal control group. These results suggest that
catecholaminergic activity might be associated with psychological stress in normal subjects. Furthermore, Immune systems are
considered to be influenced by psychological stress, actually, it
has been reported that psychological stress was associated with
the alteration of plasma levels of cytokines such as interleukin-2
(IL-2), interleukin-6(IL-6), or tumor necrosis alpha (TNF) in
healthy subjects (Glaser et al., 1999; Kiecolt-Glacer et al., 2005).
Although a clearly correlation between mental stress and
catecholamines, BDNF, and cytokines in healthy subjects
remains unknown, psychological job stress is associated with
depressive and anxious symptoms, and occasionally leads to
depression and anxiety disorders. Thus, it is probable that

psychological job stress might influence dynamics of catecholamines, BDNF, and cytokines in not only patients with
depression or anxiety disorders but also in healthy subjects.
Therefore, we hypothesized that psychological job stress in the
workplace influences blood levels of BDNF catecholamine
metabolites, and cytokines, even in healthy volunteers. In the
present study, we examined the relationship between the
severity of psychological job stress and blood levels of
BDNF, catecholamine metabolites (HVA and MHPG), and
cytokines (IL-6 and TNF) in healthy volunteers working at a
hospital. Interestingly, we found that subjects who perceived
more psychological job stress had lower BDNF levels and
higher MHPG levels, although these were independent of the
cytokine dynamics.
1.1. Subjects and methods
Included in this study were 106 Japanese hospital workers
(48 medical doctors and 58 was nurses), none of whom fulfilled
the DSM-IV criteria for major depressive disorder, panic
disorder, generalized anxiety disorder, or adjustment disorder.
None of these subjects had received any drugs for at least the
2 weeks prior to the study. All participants were physically
healthy, and no subjects had a history of alcohol and/or drug
abuse. Of the subjects, 42 were male, and 64 were female, and
their ages ranged from 20 to 70 (mean SD: 36 12) years. The
level of perceived psychological stress was evaluated using the
Stress and Arousal Check List (SACL)Japanese version. The
SACL is a self-rating scale for assessing psychological stress
and arousal that consists of 30 adjectives expressing stress and
arousal (Mackay et al., 1978). The category of stress includes 17
items regarding psychological stress and 13 items regarding
mental arousal. A higher point score is indicative of a relatively
greater degree of psychological stress and mental arousal.
Japanese version of SACL was produced by Kumashiro (2002)
and the author demonstrated that it was suitable for evaluating
stress in the occupational health field in Japan.
Blood was drawn from the participants at 8:00 a.m. before
breakfast. We used an ethylenediaminetetraacetic acis, disodium
salt as an anticoagulant for collecting plasma samples. The plasma
was quickly separated in a centrifuge and stored at 80 C until
assayed. Plasma concentrations of HVA and MHPG were
analyzed by high-performance liquid chromatography with
electrochemical detection (HPLCECD) according to the methods previously described (Yoshimura et al., 2007a,b). Serum
BDNF levels were assayed with sandwich ELISA methods. In
brief, the serum BDNF levels were measured using a BDNF Emax
Immunoassay Kit (Promega, Madison, WI, USA) according to the
manufacturer's instructions. In short, 96-well microplates were
coated with anti-BDNF monoclonal antibody and incubated at
4 C for 18 h. The plates were incubated in blocking buffer for 1 h
at room temperature. The samples were diluted 100-fold with
assay buffer, and the BDNF standards were kept at room
temperature under conditions of horizontal shaking for 2 h,
followed by washing with the appropriate washing buffer. The
plates were incubated with anti-human BDNF polyclonal antibody at room temperature for 2 h and were then washed with

M. Mitoma et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 679685

681

Fig. 1. Negative correlation between serum BDNF levels and s-SACL scores (rho = 0.221, p = 0.022).

washing buffer. The plates were then incubated with anti-IgY

antibody conjugated to horseradish peroxidase for 1 h at room
temperature, and were again incubated in peroxidase substrate and
tetramethylbenzidine solution in order to induce a color reaction.
The reaction was stopped with 1 mol/L hydrochloric acid. The
absorbance at 450 nm was measured with an Emax automated
microplate reader. Measurements were performed in duplicate.
The standard curve was linear from 5 pg/mL to 5000 pg/mL, and
the detection limit was 5 pg/mL. Cross-reactivity with related
neurotrophins (NT-3, NT-4, NGF) was less than 3%. The intraand interassay coefficients of variation were 5% and 7%,
respectively. The recovery rate of the exogenously added BDNF
in the measured plasma samples exceeded more than 95%.
The plasma levels of IL-6 and TNF were also measured
using the quantitative sandwich enzyme assay technique with a
QuantikineR HS High Sensitivity Immunoassay kit (R and D

Systems, Minneapolis, MN, USA). A monoclonal antibody

specific for IL-6, or TNF was pre-coated onto a microplate.
Standards and samples were pipetted into the wells, and any IL-6,
or TNF present was bound by the immobilized antibody. After
all unbound substances were washed away, an enzyme-linked
polyclonal antibody specific for IL-6, or TNF was added to the
wells. Following a wash to remove any unbound antibodyenzyme reagent, the substrate solution was added to the wells.
After an incubation, an amplifier solution was added to the wells,
and color was developed in proportion to the amount of IL-6, or
TNF in the initial step. The color development was stopped and
the intensity of the color was measured using a microplate reader.
Measurements were performed in duplicate. The standard curve
was linear from 0.1 pg/mL to 10 pg/mL, and the detection limit
was 0.1 pg/mL. Intra-and interassay coefficients of variation
were 7% and 9%, respectively. The recovery rates of the

Fig. 2. Positive correlation between plasma MHPG levels and s-SACL scores (rho = 0.416, p = 0.01).

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M. Mitoma et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 679685

Fig. 3. Negative correlation between serum BDNF levels and plasma MHPG levels (rho = 0.192, p = 0.046).

exogenous added BDNF, IL-6, and TNF in the measured

plasma samples were more than 95%.
The protocol of this study was approved by the Ethics
Committee of the University of Occupational and Environmental
Health. Written informed consent was obtained from all subjects.

serum BDNF levels and plasma MHPG levels (rho = 0.192,

p = 0.046) (Fig. 3). On the other hand, no correlation was found
between plasma HVA levels and s-SACL scores or serum BDNF
levels. Furthermore, there was no correlation between plasma
levels of IL-6 or TNF and s-SACL scores.

1.2. Statistical analysis

3. Discussion

MannWhitney u-test was performed to compare plasma

levels of MHPG, HVA, IL-6, or TNF, and serum BDNF levels
between men and women. The relationship between two
variables was examined using Spearman's rank correlation
coefficients. The level of significance for the results was set at
p b 0.05.

The most interesting findings of the present study were that

patients with higher s-SACL scores had lower serum BDNF levels
and higher plasma MHPG levels. In addition, a negative correlation
was found between serum BDNF levels and plasma MHPG levels,
suggesting that psychological job stress reduces serum BDNF
levels and increases plasma MHPG levels in healthy volunteers. In
other words, it is possible that serum BDNF levels and plasma
MHPG could serve as biological markers of mental stress in the
workplaces in healthy subjects.
Previous studies investigating the effect of physical or mental
stress generally have focused on changes in blood or urinary levels
of adrenaline, noradrenaline, or their metabolites (Halbrugge et al.,
1988; Januszewicz et al., 1979). Januszewicz et al. (1979) reported
that noradrenaline and MHPG concentrations in urine as well as
blood were increased in healthy subjects following Kraepelin test.
Sumiyoshi et al. (1998) also reported that plasma HVA levels
following the administration of the Kraepelin test were significantly
lower than the pretest plasma HVA levels, and the percent change in
plasma HVA levels by the Kraepelin test positively correlated with
pretest plasma HVA levels in normal subjects, suggesting that the
reduction in plasma HVA levels by mental stress might reflect some
aspects of a dopamine-dependent restitutive system in the brain. Li
et al. (2004) reported that the initial outcome of the Uchida
Kraepelin test (UKT) is significantly correlated with baseline saliva
levels of MHPG, suggesting that saliva MHPG levels are useful
predictive marker for performance on continuous tasks requiring
full attention. Conull et al. (1995) reported evidence implicating the
noradrenergic system in the mediation of attentional processes
suggesting plasma MHPG levels could serve as a marker of

2. Results
The values (mean SD) of scores for s-SCAL, plasma levels of
MHPG and HVA, serum BDNF, and plasma levels of IL-6 and
TNF in all participants were 7.2 3.3, 5.2 3.4 ng/mL, 4.6
2.6 ng/mL, 23.3 14.7 ng/mL, 2.1 0.4 pg/mL, 2.9 1.1 pg/mL,
respectively. No differences between males and females were
observed with respect to plasma levels of MHPG (male: 5.1
3.5 ng/mL, female: 5.9 3.8 ng/mL) and HVA (males: 4.1
2.2 ng/mL, females: 4.9 2.9 ng/mL). Moreover, sex
differences were not observed in plasma levels of IL-6 (males:
1.8 0.4 pg/mL, females: 2.2 0.5 pg/mL) or TNF (males: 3.2
0.7 pg/mL, females: 2.7 1.0 pg/mL) between male (18.5
12.9 ng/mL) and female (20.7 11.4 ng/mL). No correlation was
found between plasma levels of MHPG or HVA and age. As
regards serum BDNF levels, there was also no difference between
males and females and there was no relationship between serum
BDNF levels and age. A negative correlation was found between
serum BDNF levels and scores for s-SACL (rho = 0.221,
p = 0.022) (Fig. 1). A positive correlation was found between
plasma MHPG levels and s-SACL scores (rho = 0.416, p = 0.01)
(Fig. 2). In addition, there was a negative correlation between

M. Mitoma et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 679685

psychological stress. Southwick et al. (2002) reported that

enhanced noradrenergic activity during memory consolidation is
associated with enhanced long-term memory in healthy subjects.
These results indicate that psychological stress might influence
plasma levels of catecholamines and their metabolites in healthy
subjects. In clinical populations, several reports have postulated that
depression may be associated with reduced norepinephrine activity
(Schildkraut, 1965), although normal or increased MHPG levels
have also been reported in some studies of depressed patients
(Maas, 1978; Karege et al., 1991). It has also been reported that
state of anxiety are associated with increased central norepinephrine
activity (Mason and Fibiger, 1979; Redmond and Huang, 1979).
Hyperactivity of the brain noradrenergic system is among of the
mechanisms thought to be involved in the development and
expression of human anxiety (Charney and Redmond, 1983).
Therefore, it is reasonable to assume that a depression-associated
increase in noradrenaline could be superimposed an underlying
factor in anxious or depressed patients. This might in turn account
for the fluctuating noradrenaline levels often associated with certain
forms of depression; in some studies, increased, in others decreased
norepinephrine activity has been observed in samples of depressed
patients (Yoshimura et al., 2004). Thus, anxiety has become a factor
of interest in investigations of the possible effects on MHPG in
patients with depression. Taken together the central and peripheral
catechoaminergic systems might play important roles in mental
stress in healthy subjects as well as clinical populations.
It has been reported that serum and plasma levels of BDNF are
abnormally low in patients with depression, anxiety or a history of a
suicidal attempt (Karege et al., 2002a,b; Shimizu et al., 2003;
Kobayashi et al., 2005; Yoshimura et al., 2007a,b; Kim et al., 2007).
Serum BDNF levels in the present subjects were higher than those
in our previous studies of depressed patients (Yukimasa et al., 2006;
Yoshimura et al., 2006; 2007a). Recently, we reported finding a
negative correlation between serum or plasma BDNF levels and the
Hamilton Rating Scale for Depression (Ham-D) in depressed
patients (Yukimasa et al., 2006; Yoshimura et al., 2007a).
Furthermore, we found that treatment with antidepressants or
repetitive transcranial magnetic stimulation equally increased
plasma or serum BDNF levels to those of healthy subjects
(Yukimasa et al., 2006; Yoshimura et al., 2007a). Therefore, it is
possible that increases in serum and/or plasma BDNF levels are
biological markers of recovery from a depressive state. Even in
healthy subjects, there was large variation in serum BDNF values.
Sex and age (range: 2070 years) were independent factors with
respect to the serum BDNF levels. This is the first report indicating
psychological stress, which was associated with hyperactivity in
noradrenergic neurons, might decrease serum BDNF levels.
However, it remains unclear about the effect of the activity of
noradrenergic neurons on BDNF. We have reported that retardation-dominant patients with lower plasma MHPG levels respond
better to milnacipran, a serotonin norepinephrine reuptake inhibitor,
whereas anxiety- and agitation-dominant patients with higher
plasma MHPG levels respond better to paroxetine, a selective
serotonin reuptake inhibitor (Shinkai et al., 2004). In both types of
depressed patients, lower serum BDNF levels than those of healthy
volunteers have been observed (Yoshimura et al., 2007a). Taken
together, the results suggest that both the hyper-and the

683

hypoactivity of noradrenergic neurons may suppress BDNF

synthesis in depressed patients. Indeed, Noh et al. (1999)
demonstrated that both excessive as well as low catecholamine
levels decrease neurosynthesis in an in vitro study. However,
Chen et al. (2006) reported that norepinephrine induced BDNF
and activates the PI-3 K and MAPK cascades in embryonic
hippocampal neurons. Juric et al. (2006) also demonstrated that
monoaminergic neuronal activity up-regulated BDNF synthesis
in cultured neonatal rat astrocytes. In addition, Chronic treatment
with duloxetine, an SNRI, not only produces a marked
upregulation of BDNF mRNA and protein, but may also affect
the subcellular redistribution of the neurotrophin in the rat brain
(Calabrese et al., in press). Therefore, it is still controversial that
role of norepinephrine on the BDNF synthesis. Interestingly, we
recently reported that both paroxetine, an SSRI, and milnacipran,
an SNRI, equally increased plasma BDNF levels, suggesting that
enhancing serotonergic neurons are essential for increasing
BDNF levels (Yoshimura et al., 2007a,b).
In contrast, no associations between plasma levels of IL-6 or
TNF and SACL scores, were observed, suggesting that plasma
levels of IL-6 and TNF are independent of the severity of
psychological job stress in healthy volunteers. It has been
demonstrated that plasma levels of IL-6 and TNF are increase in
depressed patients, and decreased after treatment of those patients
with antidepressants, suggesting that both cytokines might be
markers of a depressed state (O' Brien, et al., 2007). In addition,
it has been reported that elevated peripheral IL-6 levels may be
related to psychological stress in non-clinical populations (Zhou
et al., 1993). Recently, Chandrashekara et al. (2007) reported that
plasma TNF levels are significantly low in college student with
high anxiety score. However, in the healthy volunteers in the
present study, no association was found between plasma levels of
IL-6 or TNF and psychological job stress.
In conclusion, we demonstrated that subjects with greater
psychological job stress had lower serum BDNF levels and higher
plasma MHPG levels than did subjects who suffering from less
psychological job stress. These results indicate that excessive
psychological job stress might introduce noradrenergic neuron
hyperactivity, which might also be associated with a suppression of
BDNF synthesis. However, it still remains unclear that the changes in
the serum BDNF levels and the plasma MHPG levels are the results
of psychological stress effects on peripheral, central, or both systems.
Acknowledgements
The authors wish to thank the staff of Shinmoji Hospital
(Kitakyushu, Japan) and Wakato Hospital (Kitakyushu, Japan) for
their assistance with this study.
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