The Immune-Mediated Alteration of Serotonin and Glutamate: Towards An Integrated View of Depression

FEATURE REVIEW
The immune-mediated alteration of serotonin and

glutamate: towards an integrated view of depression
N Mu ller and MJ Schwarz
Department for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universita t Mu nchen, Mu nchen, Germany
Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological
correlate of major depression (MD), recent evidence points to a pivotal role of increased
glutamate receptor activation as well. However, cause and interaction of these neurotrans-
mitter alterations are not understood. In this review, we present a hypothesis integrating
current concepts of neurotransmission and hypothalamuspituitaryadrenal (HPA) axis
dysregulation with findings on immunological alterations and alterations in brain morphology
in MD. An immune activation including increased production of proinflammatory cytokines
has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, inter-
feron-c, or tumor necrosis factor-a activate the tryptophan- and serotonin-degrading enzyme
indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders
are also associated with increased proinflammatory cytokines and increased consumption of
tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor
tryptophan through IDO activation could well explain the reduced availability of serotonergic
neurotransmission in MD. An increased activation of IDO and its subsequent enzyme
kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced
production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate
receptor. In inflammatory states of the central nervous system, IDO is mainly activated in
microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist
quinolinic acid, whereas astrocytes counteracting this metabolism due to the lack of
an enzyme of this metabolism have been observed to be reduced in MD. Therefore the type
1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads
to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly
involved in re-uptake and metabolic conversion of glutamate. The reduced number of
astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia
and an altered glutamatergic neurotransmission. Further search for antidepressant agents
should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors,
might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic
hyperfunction and antagonizing neurotoxic effects of quinolinic acid.
Molecular Psychiatry (2007) 12, 9881000; doi:10.1038/sj.mp.4002006; published online 24 April 2007
Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system;
serotonin
Glutamate in depression
Glutamatergic neurotransmission is involved in
depression and interacts with the serotonergic and
noradrenergic systems
The common therapeutic mechanism of antidepres-
sant drugs is the enhancement of serotonergic and/or
noradrenergic neurotransmission. On the basis of this
pharmacological profile of antidepressant drugs,
neurochemical research on major depression (MD)
focused on the serotonergic and noradrenergic neuro-
transmission during the last four decades.
1,2
Intense
research, however, has not yet discovered the
mechanisms causing disturbances of the monoami-
nergic neurotransmission. Moreover, the regularly
occurring non-response rate of about 30% for any
given antidepressant drug and several other consid-
erations have led to the conclusion that the mono-
amine hypothesis alone cannot explain the complete
pathomechanism of MD.
As early as in 1959, Crane
3
reported the anti-
depressant efficacy of high doses of D-cycloserine. D-
cycloserine, a partial N-methyl-D-aspartate (NMDA)
receptor agonist, acts as a NMDA receptor antagonist
in high doses. NMDA receptors are a class of ionotropic
glutamate receptors, and in recent years, the role of an
increased glutamatergic neurotransmission in the
pathophysiology of MD was brought into focus.
Consistent with the view that an increased activity
of the glutamatergic system and NMDA receptor
Received 1 February 2006; revised and accepted 8 February 2007;
published online 24 April 2007
Correspondence: Dr N Mu ller, Department for Psychiatry
and Psychotherapy, Ludwig-Maximilians-Universitat Mu nchen,
Nussbaumstr. 7, Mu nchen 80336, Germany.
E-mail: [email protected]
Molecular Psychiatry (2007) 12, 9881000
& 2007 Nature Publishing Group All rights reserved 1359-4184/07 $30.00
www.nature.com/mp
agonism is associated with depressed mood, a reduc-
tion of the glutamatergic activity, that is NMDA
receptor antagonismmight exert antidepressant effects.
NMDA antagonists such as MK-801,
4,5
ketamine,
6
amantadine
7
and others
8,9
exhibited antidepressant
effects in different animal models. Beside the above-
mentioned report on D-cycloserine, slight antidepres-
sant effects in humans have also been observed with
the NMDA receptor antagonists amantadine
10,11
and
ketamine.
12,13
Riluzole, an antiglutamatergic agent
believed to increase the glutamatergic uptake into
the astrocytes, is under intensive investigation for its
antidepressant potential.
14
A recent series of open-
labelled studies and case reports demonstrated its
efficacy.
1519
Although the glutamatergic system may influence
directly or indirectly the serotonergic and noradre-
nergic neurotransmission, there are only few data in
the literature dealing with this interaction. NMDA
receptor antagonists increase the serotonin levels in
the brain.
20,21
Several studies showed an increased
activity of the glutamatergic system in the peripheral
blood of depressive patients,
2224
although this result
could not be replicated by all authors.
25
The incon-
sistency of the findings, however, might be due to
medication effects, low statistical power and a lack of
appropriate control of diagnosis.
9
Support for increased glutamatergic activity in
depression comes from magnetic resonance spectro-
scopy: elevated glutamate levels were found in the
occipital cortex of unmedicated subjects with MD.
16
Associated with an increased level of certain neuro-
transmitter is often a downregulation of the respective
receptor. Accordingly, in the brains of suicide victims
and patients with depression, a reduced glycine
binding site of the NMDA receptor was found.
26,27
Moreover, a decrease in the NMDA agonistic MK-801
binding in bipolar patients was observed.
28
The glutamate system in depression: quinolinic acid as
a depressiogenic NMDA receptor agonist
Investigating the glutamatergic neurotransmission
and activation of the NMDA receptors, neurochemists
often forget to include the potential endogenous
NMDA agonist quinolinic acid into their considera-
tions.
The essential amino acid tryptophan is not only the
precursor of serotonin (5-hydroxytrypamine) and
melatonin, but also of the so-called kynurenine
(KYN) pathway. This quantitatively most prominent
metabolism pathway of tryptophan includes several
neuroactive intermediates, of which kynurenic acid
(KYN-A) and quinolinic acid act on the NMDA
receptor in an opposing mode. These two intermedi-
ates are alternative products of KYN degradation and
while KYN-A is an NMDA receptor antagonist,
quinolinic acid acts as an NMDA receptor agonist
via ligation at the glycine binding site.
An increase of quinolinic acid is strongly asso-
ciated with several prominent features of depression:
decrease in reaction time
2931
and cognitive deficits,
in particular difficulties in learning.
32
In an animal
model, an increase of quinolinic acid and 3-hydroxy-
kynurenine was shown to be associated with anxi-
ety.
33
A recent study in 16 patients treated with
interferon-g (IFN-a) showed that the depressive
symptoms were related to the increase of the ratio of
KYN/KYN-A. Five patients met criteria for MD. KYN
itself, however, showed no significant increase.
34
The
increase of the ratio, however, reflects that in
depressed states KYN is preferentially metabolized
to quinolinic acid compared to the KYN-A pathway.
The preferred metabolism to quinolinic acid is related
to the depressive symptoms, but not the metabolism
to KYN-A. A recent study revealed that the trypto-
phan degradation in patients suffering from MD was
increased compared with controls, whereas the KYN-
A concentration was lower. This combination of
findings suggests that the metabolism of KYN is
preferentially directed to the quinolinic pathway,
although quinolinic acid itself was not determined.
35
Beside the direct action of quinolinic acid as an
NMDA receptor agonist, increased levels of the
quinolinic acid lead to increased levels of glutamate.
The induction of quinolinic acid was shown to cause
an overrelease of glutamate in the striatum and in the
cortex, presumably by presynaptic mechanisms.
36,37
The quinolinic pathway could thus be the mechanism
involved in the increased glutamatergic neurotrans-
mission in MD.
16
Moreover, owing to the well-known
neurotoxic effects of quinolinic acid, it is discussed
that quinolinic acid is beside cortisone respon-
sible for neurodegeneration observed in chronic
depressive patients.
38
The role of indoleamine 2,3-dioxygenase in depression
The rate-limiting step in initialization of the KYN
pathway is the nearly ubiquitously expressed indole-
amine 2,3-dioxygenase (IDO) (or the tryptophan
dioxygenase in the liver). The further conversion of
KYN to either KYN-A or 3-hydroxykynurenine, the
precursor of quinolinic acid, is mediated by the
enzymes kynurenine aminotransferase and kynure-
nine monooxygenase, (KMO, sometimes reffered to
as kynurenine hydroxylase), respectively. The activity
of both, IDO and KMO, underlie strong regulation
by cytokines. Proinflammatory cytokines such as
IFN-g, interleukin-1 (IL-1), or tumor necrosis factor-a
(TNF-a) are potent inducers of IDO, whereas anti-
inflammatory cytokines such as IL-4 and IL-10
are IDO inhibitors.
39
Besides IFN-g and TNF-a, other
proinflammatory molecules such as prostaglandin
E
2
(PGE
2
) synergistically induce an increase of
IDO activity.
4042
This close relationship between immune system
and the KYN pathway is reflected by its crucial role in
inflammation. Tryptophan is essential for the survival
of infectious microbes, such as bacteria, and the
consumption of tryptophan plays a pivotal role
during infectious diseases.
4345
Owing to this need,
the withdrawal of tryptophan from an inflammatory
locus is part of the immune defense. Moreover, the
Immune-mediated alteration of serotonin and glutamate
N Muller and MJ Schwarz
989
Molecular Psychiatry
activity of IDO is an important regulatory component
in the control of the bodies own defense system, since
IDO activity induces a halt in the lymphocyte cell
cycle due to the catabolism of tryptophan.
46,47
Within the central nervous system (CNS), only
microglial cells and invading monocytes have the
complete set of enzymes in the pathway necessary to
produce quinolinic acid.
48,49
In a model of infection,
the highest concentrations of quinolinic acid are
found in the gray and white matter of the cortex but
not in subcortical areas indicating that high levels of
quinolinic acid may lead to cortical dysfunction.
32
Peripheral immune stimulation, however, under
certain conditions also lead to increased CNS con-
centration of quinolinic acid.
48
During a local inflam-
matory CNS process, the quinolinic acid production
in the CNS increases, but the blood levels remain
unchanged.
32
The local quinolinic acid production
correlates with the inflammatory marker b2-micro-
globulin. Local CNS concentrations of quinolinic acid
are able to exceed the blood levels by far.
32
Owing to the fact that tryptophan availability is the
rate-limiting factor in the serotonin synthesis,
45
it has
been hypothesized that a cytokine-induced, IDO-
mediated decrease of central nervous tryptophan
availability may lead to a serotonergic deficiency.
45
Moreover, serotonin can be directly metabolized by
IDO (IDO catalyses the oxidative cleavage of the
indole ring, its substrate specificity also includes
serotonin.).
50
Therefore, an enhanced production of
quinolinic acid through increased IDO activity may
not only lead to an amplified glutamatergic neuro-
transmission as stated above, but may also influence
the serotonergic neurotransmission.
Considering the important role of the immune
system in the regulation of quinolinic acid formation,
the question arises, if an immune activation is
associated with MD. The following section will
provide some evidence for the functional relationship
between inflammation and depression.
The inflammatory hypothesis of depression
Sickness behavior
An immunological model of MD is sickness beha-
vior, the non-specific reaction of the organism to
infection and inflammation. Sickness behavior is
characterized by weakness, malaise, listlessness,
inability to concentrate, lethargy, decreased interest
in the surroundings and reduced food intake all of
which are depression-like symptoms. The sickness-
related psychopathological symptomatology during
infection and inflammation is mediated by proin-
flammatory cytokines such as IL-1, IL-6, TNF-a and
IFN-g. Their active pathway from the peripheral
immune system to the brain is via afferent neurons
and through direct targeting of the amygdala and
other brain regions after diffusion at the circumven-
tricular organs and choroid plexus.
51
Undoubtedly,
there is a strong relationship between the cytokine
system and the neurotransmitter system, but a more
differentiated analysis may be required to understand
the specific mechanisms underlying the heterogenous
disease entity of MD.
In humans, the involvement of cytokines in the
regulation of the behavioral symptoms of sickness
behavior has been studied by application of the
bacterial endotoxin lipopolysaccharide (LPS) to human
volunteers.
52
LPS, a potent activator of proinflam-
matory cytokines, was found to induce mild fever,
anorexia, anxiety, depressed mood, and cognitive
impairment. The levels of anxiety, depression and
cognitive impairment were found to be related to the
levels of circulating cytokines (see Table 1).
52,53
Side effects of cytokine therapies
A depressive syndrome including suicidal ideations
is a common side effect of cytokine administration,
for example, IFN-a in the therapy of hepatitis C or
malignant melanoma.
5458
During these therapies, IDO
is activated and the tryptophan metabolism increases.
The psychopathological changes seem to be closely
related to the tryptophan metabolism: patients devel-
oping more severe depressive symptoms during IFN-a
showed a more pronounced increase in tryptophan
metabolism.
59,60
Moreover, two distinct psychopatho-
logical syndromes induced by IFN-a therapy have
been described: one syndrome characterized by
changes in mood and cognition, and another char-
acterized by psychomotor slowing, fatigue, sleep
disturbances and anorexia.
61
The mechanism, how-
ever, is not yet fully elucidated.
62,63
Activation of the immune system in MD
The characteristics of the immune activation in MD
include increased numbers of circulating lympho-
cytes and phagocytic cells, upregulated serum levels
of parameters indicating activated immune cells (for
example, soluble IL-2 receptor), higher serum con-
centrations of positive acute phase proteins (APP),
coupled with reduced levels of negative APP, as well
as an increased release of proinflammatory cytokines,
such as IL-1, IL-2, TNF-a and IL-6 through activated
macrophages and IFN-g through activated T cells.
6470
Increased numbers of peripheral mononuclear cells
have been described by different groups of research-
ers.
7173
According to these findings, an increased
secretion of neopterin has been described by several
Table 1 Cytokines of the polarized immune response
Type 1
cytokines
Type 2
cytokines
Monocyte-derived
proinflammatory
cytokines
IL-2 IL-4 IL-1
IL-12 IL-13 IL-6
IFN-g [IL-10]
Abbreviations: IFN-g; interferon-g; IL, interleukin.
IL-10 is partly a Type 2 cytokine.
990
groups of researchers.
7477
Neopterin is a sensitive
marker of the cell-mediated immunity. The main
source of neopterin is monocytes/macrophages.
In particular, the group of Maes described an
increase of the inflammatory response system and
observed a relationship between proinflammatory
immune markers, the severity of depression and
measures of hypothalamuspituitaryadrenal (HPA)
axis hyperactivity.
7880
As genetics play a role in MD,
the genetics of the immune system in relation to MD
has also been investigated. Certain cytokine gene
polymorphisms, for example, in genes coding for IL-1
and TNF-a, may confer a greater susceptibility to
develop MD.
8183
The production of IL-2 and IFN-g is the typical
marker of a type 1 immune response. IFN-g is
produced in greater amounts by lymphocytes of
patients with MD compared to healthy controls.
84
In
depressed patients, higher plasma levels of IFN-g
accompanied by lower plasma tryptophan availabil-
ity,
76
as well as increased IFN-g/IL-4 and IFN-g/TGF-b
ratios
85
have been described. However, a recent study
inversely reported an enhancement of type 2 cyto-
kines IL-4 and IL-13 together with a reduction of type
1 cytokines IL-2 and IFN-g in depression.
86
The latter
findings were discussed as being related to the
elevated cortisol levels, which were accompanied by
elevated TNF-a levels. On the other hand, the
washout time for antidepressant medication anti-
depressants increase the type 2 cytokine production
was only 3 weeks in this study. Data on IL-2 in MD are
mainly restricted to the estimation of its soluble
receptor, sIL-2R, in the peripheral blood. Increased
soluble IL-2-receptors (sIL-2R) levels reflect an in-
creased production of IL-2. The blood levels of sIL-2R
were repeatedly found to be higher in MD pa-
tients
65,66,87
as well as the in vitro production of IL-2.
88
According to the sickness behavior hypothesis, the
cytokines TNF-a, IL-1 and IL-6 have frequently been
investigated in MD. A considerable number of studies
showed elevated serum levels of TNF-a
70,86,8993
and
IL-1b
9496
in depressed patients, whereas only few
investigators reported unchanged levels of these
cytokines.
97
A study on elevated mRNA levels of
TNF-a in peripheral mononuclear cells of depressed
patients confirms the majority of findings on elevated
serum levels.
98
Levels of IL-1b are also elevated in
cerebrospinal fluid (CSF), whereas TNF-a levels are
not altered in CSF of depressed patients.
89
As a product of activated monocytes and macro-
phages, IL-6 is one of the most frequently investigated
immune parameters in MD. The majority of reports
demonstrate a markedly higher in vitro IL-6 produc-
tion,
80,94
or higher serum IL-6 levels in depressed
patients
65,87,93,99104
as well as IL-6 mRNA expression
in leukocytes.
98
The elevation of IL-6 seems to be
especially profound in the morning. Additionally, the
circadian rhythm of IL-6 secretion is altered in
depressed patients.
105
Elevated whole blood IL-6
levels in unmedicated depressed patients were
demonstrated to be related to treatment non-response
to antidepressant administration, whereas patients
with subsequent remission showed markedly lower
IL-6 levels.
90
Higher plasma IL-6 concentrations were
also found in cancer patients with depression,
compared with cancer patients without depression
or healthy control subjects.
106
Contradictory results
are very few indicating reduced,
107
or not altered,
serum IL-6 levels.
97,108,109
The potential influence of
possibly interfering variables, such as age, smoking,
gender, recent infections and prior medication (in-
cluding insufficient washout period) to IL-6 release
and concentration must be considered.
110
An age-
related increase of IL-6 serum values was reported in
patients with MD,
111
but also elderly depressed
patients exhibit higher IL-6 serum levels compared
with control persons of comparable age.
92
In contrast,
CSF levels of IL-6 and soluble IL-6 receptor were
found to be markedly reduced in geriatric patients
suffering from depression.
112
Another study investi-
gating depressed patients of age 1866 could not find
any alteration of IL-6 levels in the CSF.
113
Levine et al.
89
compared serum and CSF cytokine levels in depressed
patients and healthy control persons and found
significantly elevated serum levels of IL-6, but de-
creased IL-6 levels in CSF. Thus, the elevated IL-6
secretion may be restricted to the peripheral compart-
ment. On the other hand, IL-6 acts locally in a paracrine
manner and CSF levels may not be representative for
local cellular effects of IL-6 in the CNS.
Altogether, the three cytokines, typically inducing
sickness behavior appear to be elevated at least in the
peripheral blood of depressed patients. Both, IL-1 and
TNF-a are strong inducers of IDO. Thus IDO activity
may be enhanced in depressed patients through these
cytokines. Although IL-6 does not directly act on IDO,
its elevated levels in serum may contribute to IDO
activation within the CNS by the stimulatory effect on
PGE
2
, which acts as cofactor in the activation of IDO.
Recent investigations confirmed that the bloodbrain
barrier (BBB) is not a divider preventing signal
transduction, but rather the transducer itself. In the
endothelial and perivascular cells of the BBB, up-
stream signaling molecules such as proinflammatory
cytokines are switched to the downstream mediator
PGE
2
.
114
This fits with a report on the correlation of
increased in vitro IL-6 production with decreased
tryptophan levels in depressed patients emphasizing
the influence of IL-6 on the serotonin metabolism
(see Table 2).
80
Moreover, clinical studies have observed higher
levels of type 1 cytokines in suicidal patients. In a
small study, distinct associations between suicidality
and type 1 immune response and a predominance of
type 2 immune parameters in non-suicidal patients
were observed.
115
An epidemiological study also
hypothezized that high IL-2 levels are associated with
suicidality.
116
One study showed increased levels of
serum sIL-2R in medication-free suicide attempters
irrespective of the psychiatric diagnosis,
117
and
treatment with high-dose IL-2 has been associated
with suicide in a case report.
118
991
Different types of MD were observed to exhibit
different immune profiles, the subgroup of melan-
cholic depressed patients showed a decreased type 1
activation accompanied with a marked activation of
the HPA axis, whereas the non-melancholic de-
pressed patients showed signs of inflammation such
as increased monocyte count and increased levels of
IL-1b and a2-macroglobulin.
73,119
Moreover, the plasma levels and expression in the
brain of intercellular adhesion molecule-1 (ICAM-1)
seem to be related to depression: both, in patients
treated with IFN-a
57
and in patients after acute
coronary syndromes,
120
soluble ICAM-1 levels were
observed to be associated with depressive symptoms.
Moreover, increased expression of ICAM-1 was found
in the prefrontal cortex of elder depressive patients.
121
ICAM-1 is a type 1 related protein and a cell adhesion
molecule expressed on macrophages and lympho-
cytes. Increased expression of ICAM-1 is observed in
inflammatory processes, it promotes the influx of
peripheral immune cells through the BBB.
122
By this
mechanism, macrophages and co-stimulatory lym-
phocytes can invade the CNS, further increasing the
proinflammatory immune response. Inflammation is
associated with increased invasion of macrophages/
microglia in the CNS.
123
Beside the above-mentioned
signal transducing effect of the BBB, the direct entry
of activated immune cells may therefore also con-
tribute to an enhanced proinflammatory signal in the
CNS.
Postpartum depression as model for type 1/type 2
imbalance
Pregnancy is immunologically characterized by a
dominance of the type 2 immune response of
the mother to protect the fetus from abortion, the
maternal organism developing immune tolerance
against the non-self-organism of the baby.
124,125
After
delivery, an activation of the type 1 response of
the maternal immune system takes place.
126,127
This
type 1-dominated maternal immune re-balancing was
found to be associated with the postpartum blues,
126
a
state found in 2075% of mothers,
128,129
or the
postpartum depression, a state found in 1015% of
mothers.
130
After delivery, an increase of the proin-
flammatory immune response was described.
126,127
Accordingly, postpartum blues is associated with
increased activation of the proinflammatory immune
response, increased activity of the IDO and a delay in
the increase of postpartum tryptophan levels com-
pared with mothers without the blues.
126,131
Symp-
toms of depression and anxiety in the early
puerperum are significantly related to the increase
of the proinflammatory cytokine IL-8.
126
Postpartum
depression is associated with the activation of the
proinflammatory type 1 immune response and a lack
of tryptophan.
132,133
Prostaglandins and depression
PGE
2
is a molecule of the proinflammatory cascade. It
stimulates the production of proinflammatory cyto-
kines, for example, IL-6, the expression of cycloox-
ygenase-2 (COX-2), and as a cofactor the
expression of IDO. Therefore an increased secretion
of PGE
2
would be expected in depressive disorders.
Increased levels of PGE
2
have indeed been observed
in CSF, in serum and in saliva of depressed
patients.
134136
In vitro studies likewise show an
increased PGE
2
secretion from lymphocytes of de-
pressed patients compared with healthy controls.
102
Twenty years ago, it was suggested that antidepres-
sants inhibit PGE
2
.
137
A recent in vitro study has
shown that both tricyclic antidepressants and selec-
tive serotonin inhibitors attenuated cytokine-induced
PGE
2
and nitric oxide production by inflammatory
cells from synovial tissue.
138
Stress and the immune system in MD
Stress, cytokines and HPA axis activation
It has been proposed that stress may act as a
predisposing factor for MD. An impaired ability of
Table 2 Major cytokine alterations in major depression
Cytokine In vitro production Peripheral blood CSF
Unmedicated Effect of antidepressants Unmedicated Effect of antidepressants Unmedicated
IL-1b mm kk mm m
IL-2 and sIL-2R m k m m
IL-4 k mk m
IL-6 and sIL-6R mm kk mm kk mk
IL-10 m mm
IFN-g m kk m k
TNF-a mm kk mm kk 2
TGF-b m k m
Abbreviations: IFN-g; interferon-g; IL, interleukin; sIL-6R, soluble IL-6-receptors; TNF-a, tumor necrosis factor-a; TNF-b,
tumor necrosis factor-b.
mm or kk means frequently repeated, relatively consistent data for elevation or decrease, respectively; m or k means less
consistent data; 2 means no changes; km means controversial results.
992
stress coping has repeatedly been described in
patients with MD, even before the first exacerbation
of the disorder, and psychosocial stressors frequently
precede the onset of MD.
139
Additionally, an altered
HPA axis physiology and dysfunctions of the extra-
hypothalamic corticotrophin-releasing hormone
(CRH) system have been consistently found in
subjects with MD.
140
Activation of the HPA axis is
one of the best-documented changes in MD.
141
Several
studies demonstrate that MD patients exhibit higher
baseline cortisol levels or at least much higher
cortisol levels during the recovery period after
psychological stress.
142
Proinflammatory cytokines such as IL-1 and IL-6
are known to stimulate the HPA axis via hypothala-
mic neurons. For example, the release of the CRH and
growth hormone-releasing hormone (GHRH) is stimu-
lated by IL-1,
143,144
the central IL-1 upregulation leads
to stimulation of CRH, the HPA axis and the
sympathetic nervous system.
145,146
IL-6 is also in-
volved in modulation of the HPA axis and increased
availability of IL-6 in the hypothalamus is associated
with increased HPA activity.
147
Proinflammatory
cytokines additionally inhibit the function of the
glucocorticoid receptor (GR).
148
This functional rela-
tionship was demonstrated recently by Fitzgerald
et al.,
93
who demonstrated a reduced vasoconstriction
response upon topical corticosterone application on
the skin in antidepressant-resistant depressive pa-
tients. This reduced GR response was related to high
serum TNF-a and IL-6 levels. Since psychological or
physical stress was shown to result in an enhanced
IL-6 secretion in the peripheral immune system,
149151
the functional relationship between cytokines and
HPA axis activity is of pivotal interest in MD research.
Psychological stress not only directly induce the
activity of the HPA axis, but may also induce it
indirectly through increased IL-6 levels. An activa-
tion of the immune system and psychological stress
together may, therefore, lead to an overwhelming HPA
axis stimulation. Beside the relationship between
HPA axis hormones and cytokines, glucocorticoids
stimulate the tryptophan metabolism through the
KYN pathway in the liver, directly resulting in
decreased CNS concentrations of serotonin.
152
Stress and CNS immune system
The effect of chronic stress on the peripheral immune
system and its relevance for MD has extensively been
discussed.
153
Recent in vivo evidence now suggests
that stress-induced elevation of glucocorticoids also
enhances immune function within the CNS through
microglia activation and proliferation. According to
the type 1/type 2 hypothesis of astrocytes and
microglia, stress is associated with microglia activa-
tion, but also with a loss in the number and volume of
astrocytes.
154
Animal studies show that stress induces
an enhanced expression of proinflammatory factors
such as IL-1b,
155,156
macrophage migration inhibitory
factor
157159
and COX-2
160
in the brain. Elevation of
these proinflammatory factors is accompanied with
dendritic atrophy and neuronal death within the
hippocampus,
161,162
which are also found in brains of
subjects with MD. These detrimental effects of
glucocorticoids in the CNS are mediated by a rise in
extracellular glutamate
163,164
and subsequent over-
stimulation of the NMDA receptor. Such an over-
stimulation of the NMDA receptor results in
excitotoxic neuronal damage.
165
Nair and Bonneau
166
could demonstrate that restraint-induced psychologi-
cal stress stimulates proliferation of microglia, which
was prevented by blockade of corticosterone synth-
esis, the GR or the NMDA receptor. These data show
that stress-induced microglia proliferation is
mediated by corticosterone-induced, NMDA recep-
tor-mediated activation within the CNS. Moreover,
NMDA receptor activation during stress leads again to
increased expression of COX-2 and PGE
2
. Both,
COX-2 and PGE
2
per se are able to stimulate microglia
activation. Therefore, a vicious circle may be in-
duced, if the stress response is not limited, as it is
discussed in MD.
Astrocytes, microglia and type 1/type 2 response
The cellular sources for the polarized immune
response in the CNS are astrocytes and microglia
cells.
167
Microglial cells, deriving from peripheral
macrophages, secrete preferably Th1 cytokines
such as IL-12, whereas astrocytes inhibit the produc-
tion of IL-12 and other type 1 cytokines and secrete
the type 2 cytokine IL-10.
168,169
The type 1/type 2
imbalance in the CNS might be represented by an
imbalance in the activation of microglial cells and
astrocytes. Since the type 1 activation predominates
the response in the peripheral immune system in
depression, a dominance of microglial activation
compared to astrocyte activation should be observed
in depression.
Glial reductions were consistently found in brain
circuits known to be involved in mood disorders,
such as in the limbic and prefrontal cortex.
170174
Although some reports did not differentiate between
the loss of microglial cells or astrocytes, this differ-
ence is crucial due to the different effects of the type
1/type 2 immune response. Recent studies show that
in particular astrocytes are diminished in MD,
175177
although the data are not fully consistent.
178
A loss of
astrocytes was particularly observed in younger
depressed patients: the lack of glial fibrillary acidic
acid (GFAP)-immunoreactive astrocytes reflects a
lowered activity of responsiveness in those cells.
176
A reduced expression of the astrocyte-specific GFAP
indicating a loss of astrocytes,
179
was found in many
cortical layers and in different sections of the
dorsolateral prefrontal cortex, but also in the cerebel-
lum in MD.
179,180
Loss of astrocytes seems also to be associated with
an impaired re-uptake of glutamate from the extra-
cellular space into astrocytes by high-affinity gluta-
mate transporters, which are primarily found on
astrocytes.
181,182
Impaired glutamate re-uptake from
993
the synaptic cleft by astroglia prolongs synaptic
activation by glutamate.
183,184
Pharmacologic intervention in MD is associated
with downregulation of the proinflammatory
immune response
Antidepressant pharmacotherapy
In animal experiments, a modulatory, mostly inhibi-
tory effect of serotonin reuptake inhibiting drugs on
activation of proinflammatory immune parameters
was demonstrated.
185188
Several antidepressants induce in vitro a shift from
a type 1 to a type 2, that is from a proinflammatory to
an antiinflammatory immune response.
189
Antide-
pressants such as clomipramine, fluoxetine, imipra-
mine, mianserine, sertraline, trazodone and
venlafaxine significantly reduced the IFN-g/IL-10
ratio, reflecting the type 1/type 2 relationship.
190192
Even in depressed patients suffering from multiple
sclerosis, antidepressant treatment was associated
with a reduced in vitro IFN-g production.
193
Other
in vitro studies found a significantly reduced produc-
tion of IFN-g, IL-2, sIL-2R, and IL-10 after antidepres-
sant treatment compared to pre-treatment values
in whole blood assays.
72,194
Another study observed
a downregulation of the IL-6 production during
amitriptyine treatment, whereas the TNF-a produc-
tion decreased significantly only in treatment
responders.
90
However, there are also studies
showing no effect of antidepressants on the in vitro
production of cytokines.
195
Methodological differ-
ences may be accounted for these inconclusive
results. Overall, it can be concluded that antidepres-
sants of different classes show a downregulation of
the type 1 cytokine production in vitro.
195
In micro-
glial and in mixed glial cultures, amitriptylin and
nortriptylin were observed to inhibit the release of
IL-1b and TNF-a.
196
Regarding the serum levels of MD patients, several
researchers reported a decrease of IL-6 during treat-
ment with serotonin re-uptake inhibitors
197,198
and
other antidepressants.
101
Myint et al.
85
reported an
increase of the regulating, anti-inflammatory Th3-
cytokine TGF-b together with a reduction of the
IFN-g/IL-4 ratio after antidepressant therapy. Mark-
edly reduced TNF-a serum levels were found in
remitted depressed patients after chronic antidepres-
sant therapy for at least half a year.
199
However, there
are again some conflicting results, showing no effect
of certain antidepressants on serum levels of different
cytokines.
65,100
Regarding the relationship between IL-6 and PGE
2
as mentioned above, an inhibiting action of anti-
depressants on PGE
2
would be expected.
200
Twenty
years ago, it was suggested that antidepressants
inhibit PGE
2
.
137
A recent in vitro study has shown
that both tricyclic antidepressants and selective
serotonin inhibitors attenuated cytokine-induced
PGE
2
and nitric oxide production by inflammatory
cells from synovial tissue.
138
Immunological effects of non-pharmacologic treatment
strategies
Electroconvulsive therapy was found do downregu-
late increased levels of the proinflammatory cytokine
TNF-a in patients with MD as antidepressant phar-
macotherapy.
201
During sleep, a shift to the type 1 immune response
takes place,
202
for example, an increase of TNF-a and
IL-12 and a decrease of the type 2 IL-10-producing
monocytes were observed. In contrary, sleep depriva-
tion a therapeutic paradigma in depression
blocked the increase of type 1 and decrease of type
2 cytokines (T Lange and S Dimitrov, personal
communication). Thus, sleep deprivation may exert
therapeutic effects through a low suppression of
type 1 cytokines in MD.
Cyclooxygenase-2 inhibition as a possible anti-
inflammatory therapeutic approach in depression
Owing to the increase of proinflammatory cytokines
and PGE
2
in depressed patients and the relationship
to depressive symptoms, anti-inflammatory treatment
would be expected to show antidepressant effects in
these patients. In particular, the COX-2 inhibitors
seem to show advantageous results: animal studies
show that COX-2 inhibition can lower the increase of
the proinflammatory cytokines IL-1b, TNF-a and of
PGE
2
, but it can also prevent clinical symptoms such
as anxiety and cognitive decline, which are associated
with this increase of proinflammatory cytokines.
203
Moreover, treatment with the COX-2 inhibitor
celecoxib but not with a COX-1 inhibitor prevented
the dysregulation of the HPA axis, in particular the
increase of cortisol, one of the biological key features
associated with depression.
203,204
This effect can be
expected because PGE
2
stimulates the HPA axis in the
CNS
205
and PGE
2
is inhibited by COX-2 inhibition.
Moreover, the functional effects of IL-1 in the CNS
sickness behavior being one of these effects were
also shown to be antagonized by treatment with a
selective COX-2 inhibitor.
206
Additionally, COX-2 inhibitors influence either
directly or via CNS immune mechanisms the CNS
serotonergic system. In a rat model, treatment with
rofecoxib was followed by an increase of serotonin in
the frontal- and the temporo-parietal cortex,
207
and
the non-specific COX-inhibitor diclofenac attenuated
the IFN-a-induced enhancement of serotonin turn-
over in rat prefrontal cortex.
208
Since the lack of
serotonin is one of the pinpoints in the pathophysio-
logy of depression, a clinical antidepressive effect of
COX-2 inhibitors would be expected due to this
effect. In an other animal model of depression, an
increased expression of COX-2 in the hippocampus
was observed; preliminary data from this group
point to an antidepressant effect of COX-2 inhibitors
in this model.
209
A possible mechanism of the
antidepressant action of COX-2 inhibitors is the
inhibition of the release of IL-1 and IL-6. Moreover,
COX-2 inhibitors also protect the CNS from effects of
quinolinic acid.
210
994
Accordingly, a clinical antidepressant effect of
rofecoxib was found in 2228 patients with osteoar-
thritis, 15% of them showing a comorbid depressive
syndrome, which was evaluated by a specific depres-
sion self-report. Comorbid depression was a signifi-
cant predictor for worse outcome regarding the
ostheoarthritis-related pain to rofecoxib therapy.
Surprisingly, there was a significant decrease in the
rate of substantive depression during therapy with
25 mg rofecoxib from 15% to 3% of the patients.
211
Moreover, an own randomized double-blind pilot
add-on study using the selective COX-2 inhibitor
celecoxib in MD showed a significant therapeutic
effect of the COX-2 inhibitors on depressive symp-
toms.
212
Although those preliminary data have to be
interpreted cautiously and intense research has to be
provided to evaluate further the therapeutic effects of
COX-2 inhibitors or other anti-inflammatory drugs in
MD, those results are encouraging for further studies
dealing with the inflammatory hypothesis of depres-
sion with regard to pathogenesis, course and therapy.
The class of COX-2 inhibitors, however, may exert
antidepressant effects not only by regulation of
cytokines and PGE
2
, but also by effects on the GR
of the HPA axis,
204
and the effects of COX-2 inhibition
to NMDA receptor and glutamatergic neurotrans-
mission.
213
Conclusion
There is strong evidence for the view, that the
interactions of the immune system, IDO and the
serotonergic system, and the glutamatergic neuro-
transmission play a key role in depression. These
factors contribute to the overweight of NMDA agon-
ism in depression. The differential activation of
microglia cells and astrocytes may be an additional
mechanism contributing to this imbalance. The
immunological imbalance results in an increased
PGE
2
production and probably also in an increased
COX-2 expression. However, several gaps, for exam-
ple, the roles of genetics, disease course, sex, different
psychopathological states, and so on have to be
bridged by intense further research. Moreover, COX-
2 inhibition is only one example for possible
therapeutic attempts acting on these mechanisms,
although not only anti-inflammatory effects contri-
bute to the therapeutic outcome. The effects of COX-2
inhibition in the CNS as well as the different
components of the inflammatory system, the KYN
metabolism and the glutamatergic neurotransmission
need careful further scientific evaluation.
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