Cytokines and schizophrenia: Microglia hypothesis

of schizophrenia
Akira Monji, MD, PhD,* Takahiro Kato, MD, PhD and Shigenobu Kanba, MD, PhD
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

The etiology of schizophrenia remains unclear, while

there has been a growing amount of evidence for the
neuroinflammation and immunogenetics, which are
characterized by an increased serum concentration of
several pro-inflammatory cytokines. Despite the fact
that microglia comprise only <10% of the total brain
cells, microglia respond rapidly to even minor pathological changes in the brain and may contribute
directly to the neuronal degeneration by producing
various pro-inflammatory cytokines and free radicals.
In many aspects, the neuropathology of schizophrenia has recently been reported to be closely associatedwith microglial activation. Previous studies have

CHIZOPHRENIA IS A chronic and often debilitating illness that affects approximately 1% of the
world population. In addition to severely disrupting
the life of patients and their families, schizophrenia
imposes a great cost on society in terms of productivity loss and treatment-related expenses.1,2 The
etiology of schizophrenia remains elusive, while
dopaminergic hyperfunction in the limbic system
and dopaminergic hypofunction in the frontal cortex
as well as glutamatergic hypofunction are known
to play important roles in the pathophysiology of
schizophrenia.

*Correspondence: Akira Monji, MD, PhD, Department of

Neuropsychiatry, Graduate School of Medical Sciences, Kyushu
University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Email: amonji@hf.rim.or.jp
Accepted 27 January 2009.

shown the inhibitory effects of some typical/atypical

antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both
of which have recently been known to cause a
decrease in neurogenesis as well as white matter
abnormalities in the brains of patients with schizophrenia. The microglia hypothesis of schizophrenia
may shed new light on the therapeutic strategy for
schizophrenia.
Key words: antipsychotics, cytokine, inflammation,
microglia, schizophrenia.

We herein review the relationship between cytokines and schizophrenia. We also propose the microglia hypothesis of schizophrenia (Fig. 1), and suggest
a therapeutic strategy for schizophrenia through the
inhibition of microglial activation.

CYTOKINES AND MICROGLIA

Cytokines serve cellular communication. Released for
auto- and paracrine signaling, membrane-associated
for cellcell interaction, or occasional biological
information through body fluids, these small proteins regulate cell growth, survival, differentiation,
and activities. Several cytokines, including growth
factors, and their receptors have been found to be
present and functional in the central nervous system
(CNS).3 Among them are tumor necrosis factor-a
(TNF-a), interferon (IFN), interleukin 1 (IL-1), IL-2,

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Psychiatry and Clinical Neurosciences 2009; 63: 257265

Stressful life events (e.g. birth, trauma, infection etc)

Stimulating agents of microglia
(e.g. LPS, IFN- etc)
Resting microglia
(ramified type)

Activated microglia
Cytokines
TNF-
IL-1
IL-6
etc

Free Radicals
Nitric Oxide (NO)
Superoxide (O2-)
Peroxynitrite (ONOO-)
etc

Neuronal cells
Progenitor cells
Oligodendrocytes

Neuronal degeneration, decreased neurogenesis, white matter abnormalities etc

Pathophysiology of Schizophrenia
Figure 1. Microglia hypothesis of schizophrenia. Immunological/inflammatory activators such as interferon (IFN)-g and
lipopolysaccharide (LPS), which are induced by varieties of stress events and life events, activate microglia in the central nervous
system. Activated microglia release pro-inflammatory cytokines and free radicals. These mediators are known to cause neuronal
degeneration, white matter abnormalities and decreased neurogenesis. These neuronmicroglia interactions may thus be one of the
important factors in the pathophysiology of schizophrenia. IL, interleukin; TNF, tumor necrosis factor.

-3, -4, -6, -10, -12, -15, and -18, transforming growth
factor-b (TGF-b), colony-stimulating factors such
as macrophage colony-stimulating factor (M-CSF),
platelet-derived growth factor (PDG), epidermal
growth factor (EGF), fibroblast growth factor (FGF),
insulin-like growth factor (IGF), and neurotrophic
factors such as nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), and neurotrophins (NT-3 and NT-4). An increasing body of
evidence relates to the evergrowing family of
chemokines. Neurodevelopmental roles are postulated for various cytokines. Some also modulate neuronal activities in the mature CNS and participate in

neuro-immuneendocrine communication. Constitutive functions of typical immunoregulators in

the day-to-day physiology of the normal immuneprivileged CNS are still unclear, while certain cytokines appear in the affected brain region and the
cerebrospinal fluid (CSF) when the CNS homeostasis
is disturbed as a result of trauma, stroke, ischemia,
infection, or degenerative processes. Increased cytokine levels in the CNS may result from bloodbrain
barrier (BBB) disruption or synthesis by invading
immune cells, both of which originate from extraneuronal sources. Nevertheless, most, if not all, neuropathologies are to various extents associated with the

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Psychiatry and Clinical Neurosciences 2009; 63: 257265

activation of microglia and astrocytes. Microglia are

the primary reservoirs of pro-inflammatory cytokines
such as IL-6, TNF-a and IFN-g and act as antigenpresenting cells in the CNS.4
Despite the fact that microglia comprise only
<10% of the total brain cells, microglia respond
rapidly to even minor pathological changes in the
brain and may contribute directly to neuronal degeneration by producing various pro-inflammatory
cytokines and free radicals.5,6 In contrast, the neuron
microglia interaction has been reported to orchestrate
the balance between synaptogenesis and neuronal
death during the brains development and injuries.7

NEUROINFLAMATION IN
SCHIZOPHRENIA: MICROGLIA
HYPOTHESIS OF SCHIZOPHRENIA
There has been more evidence indicating the significance of neuroinflammation and immunogenetics
in schizophrenia, characterized by an increased
serum concentration of several pro-inflammatory
cytokines.812 Increased serum concentrations of IL-2,
IL-6 and IL-8 have been observed in schizophrenia
patients,13,14 and immunomodulatory drugs such as
cyclooxygenase-2 (COX-2) inhibitors have recently
been reported to have beneficial effects on schizophrenia symptoms.15,16 Increased serum and CSF
levels of S100B, a suitable marker for the destruction
of CNS tissue in the context of different diseases
including neurodegenerative disorder, were reported
in schizophrenia patients with negative symptoms or
a chronic duration.17 Epidemiologic studies demonstrate a significant environmental impact of maternal
viral infection and obstetric complications on the risk
of schizophrenia. Elevated inflammatory process is
known to play an important role in these circumstances.18,19 A recent DNA microarray study has
shown the increased expression of genes related to
immune and chaperone function in the prefrontal
cortex in schizophrenia.8 Another recent study using
the prefrontal cortex in schizophrenia has shown that
the molecular basis for schizophrenia changes from
early to chronic stage, providing evidence for a changing nature of schizophrenia with disease progression.
Namely, short-term illness was associated with disruption in gene transcription, metal-binding, RNA
expression and vesicle-mediated transport, while
long-term illness was associated with inflammation,
stimulusresponse and immune functions.10

Cytokines and schizophrenia

259

Microglial activation and schizophrenia

Prolonged microglial hyperactivity may lead to neuronal apoptosis and brain damage, which are commonly seen in neurodegenerative disorders such as
Parkinsons disease (PD) and Alzheimers disease
(AD).20,21 A neurodegenerative and neurodevelopmental process is indicated in the course of schizophrenia22,23 and may be associated with microglial
activation. Hypoglutamatergic states and impaired
N-methyl-D-aspartate (NMDA) signaling underlie the
pathophysiology of schizophrenia. NMDA antagonists such as phencyclidine (PCP), ketamine, and
MK-801 offer an appropriate animal model of schizophrenia. All three NMDA antagonists are known
to induce microglial activation in the brains of
rodents.24,25
Interestingly, microglial activation or increased
microglial cellular density has also been suggested
by post-mortem studies, at least in subpopulations of
individuals with schizophrenia.2628 Highly elevated
microglial cell numbers have been demonstrated in
the anterior cingulate cortex and mediodorsal thalamus of patients with schizophrenia who had committed suicide during acute psychosis.29 Using [11C]
(R)-PK11195, a specific ligand of the peripheral
benzodiazepine-binding sites (PBBS) used for a
systematic study of microglial activation in vivo,
researchers have recently reported increased microglial activation in the gray matter of patients with
schizophrenia, which is similar to patients with neurodegenerative dementia.30,31 That positron emission
computed tomography study demonstrated that activated microglia are present in schizophrenia patients
within the first 5 years after the onset of disease.31

Neurogenesis and schizophrenia

The relationship between depression and neurogenesis has been described in general,32 while one
recent human post-mortem brain study using Ki-67
immunoreactivity indicated that the phenomenon
of neurogenesis is much more related to the pathophysiology of schizophrenia than that of depression.33 Repeated administration of PCP as well as
MK-801 has recently been reported to inhibit hippocampal neurogenesis in vivo.34,35 Mice harboring compound disruption in the neuronal PAS domain
protein 3 (NPAS3) and related NPAS1 genes manifest
behavioral and neuroanatomical abnormalities reminiscent of schizophrenia.36 Basal neural precursor

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A. Monji et al.

cell proliferation in the dentate gyrus of NPAS3

gene-deficient mice has been found to be reduced
significantly, which indicated impaired neurogenesis involved in schizophrenia.37 Disruptedin-schizophrenia 1 (DISC1) is a well-known
schizophrenia susceptibility gene. A recent study has
shown that DISC1 regulates integration of newly generated neurons in the adult brain.38 The aforementioned results indicate the close relationship between
schizophrenia and neurogenesis. With regard to neurogenesis, atypical antipsychotics, but not typical antipsychotics, induced neurogenesis in the adult brains of
rodents.35,39,40 In contrast, CNS inflammation is detrimental for adult hippocampal neurogenesis.41,42
The negative effects of inflammation on differentiation and survival of the neuronal cells are due, in
vitro, to microglia-derived TNF-a and nitric oxide
(NO).41,43 Pro-inflammatory cytokines such as Il-1b
and TNF-a have been reported to inhibit neurogenesis in vivo.44,45 In addition, in vivo, neurogenesis can
be restored by anti-inflammatory drugs such as
minocycline and indomethacin that inhibit microglial activation.41,42

Apoptosis and schizophrenia

Structural brain abnormalities have been described
extensively and consistently in schizophrenia
patients. Longitudinal studies using high-resolution
magnetic resonance imaging (MRI) to examine brain
structure have found that MRI volume changes were
progressive over time and related to the course of
illness and treatment outcome in schizophrenia
patients.4648 A recent review has shown that continuous progressive brain tissue decreases, and lateral
ventricle volume increases in chronically ill patients
with schizophrenia, until at least 20 years after the
first symptoms.49 In fact, multiple lines of evidence
combine to implicate increased susceptibility to
apoptotic death in the pathophysiology of schizophrenia. Reduced neuronal and glial cell numbers,
decreased neuropil (especially of the synapse elements), lack of gliosis, and in vivo neuroimaging
evidence of progressive gray matter loss early in the
disorder, as mentioned earlier, make apoptosis a
plausible mechanism to explain the neurodegenerative course of schizophrenia. The activation of apoptotic process can lead to a rapid neuronal death.
Emerging data, however, also indicate that sublethal
apoptotic activity can lead to a limited form of apoptosis in terminal neuritis and individual synapses to

Psychiatry and Clinical Neurosciences 2009; 63: 257265

cause elimination without cell death.50,51 Inappropriate activation of apoptosis occurs not only in the
neurons, but also in the oligodendrocytes and synapses.50 Pro-inflammatory cytokines such as TNF-a
have been well characterized as mediators of oxidative stress, and they induced apoptosis in human
cortical neuron as well as oligodendrocytes.52,53 In
addition, NO has been reported not only to directly
induce neuronal apoptosis, but also to be involved in
cytokine-mediated neuronal apoptosis.54,55 The interaction between NO and superoxide anion (O2-),
which can be generated from activated microglia,
forms peroxynitrite (ONOO-). Peroxynitrite is highly
toxic and triggers apoptotic cell death. Moreover,
high levels of NO and TNF-a may also affect synaptogenesis, synaptic plasticity and connectivity, and
the composition of synaptic membranes.56,57 The
alteration in the synaptic organization of the brain is
one of the key features of schizophrenia.58

Oligodendrocyte dysfunction
in schizophrenia
Neuroimaging studies have shown that first-episode
schizophrenia patients had a significant volume
reduction in white matter with abnormal brain connectivity.59,60 The reduced density and compromised
morphology of the oligodendrocytes as well as
signs of deviant myelination are evident in schizophrenia.61,62 Iwamoto et al. reported a functional
single-nucleotide polymorphism in the 2,3-cyclic
nucleotide 3-phosphodiesterase gene, which affects
the expression of oligodendrocyte-related genes in
schizophrenia.63 Combined with the evidence of
dysregulation of the myelination-related genes, a disruption of the oligodendrocyte function in schizophrenia is strongly implicated.64 Microglial activation
in the CNS has been implicated in the pathogenesis
of white matter disorders and it has recently been
reported that microglial cytotoxicity of oligodendrocyte is mediated through free radical-related molecules such as NO and peroxynitrite generated by
activated microglia,65,66 and inflammatory cytokines
such as TNF-a and IFN-g.53 In addition, TNF-a has
been shown to compromise the growth of oligodendrocytes and the expression of mRNA for myelin
basic protein in cultures.67 Furthermore, it inhibited
the survival and proliferation of the oligodendrocyte
progenitors and their subsequent differentiation into
mature myelinating phenotypes.68

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ANTIPSYCHOTICS AND MICROGLIAL

ACTIVATION
Atypical antipsychotics are becoming standard drugs
for the treatment of schizophrenia due to their less
adverse effects and greater effectiveness for the negative symptoms of schizophrenia.48,69 Some recent
reports have suggested the possibility of specific
atypical antipsychotics having pharmacological properties that could produce neurotrophic, neurogenetic,
or neuroprotective effects. Namely, specific atypical
antipsychotics such as olanzapine and risperidone
have been reported to decrease the reduction of
MRI volume during the clinical course of
schizophrenia.6972 Moreover, recent reports have
demonstrated that atypical antipsychotics, such as
clozapine and risperidone, decreased serum levels
of cytokines such as IL-2, IL-6 and TNF-a,73 the main
source of which in the CNS is considered to be activated microglia in schizophrenia patients. A possible
antipsychotic effect of minocycline, which is a potent
inhibitor of microglial activation, has also been
reported in patients with schizophrenia.74,75 Miyaoka
et al., using the Positive and Negative Syndrome
Scale, demonstrated statistically significant and
robust clinical improvements with minocycline as an
adjunctive therapy to antipsychotics for schizophre-

Cytokines and schizophrenia

261

nia.74,75 We thus hypothesize that antipsychotics

may have anti-inflammatory effects on microglial
activation.

Typical and atypical antipsychotics with

dopamine D2 receptor antagonism
To the best of our knowledge, there have been only a
few previous studies on the effect of antipsychotics
on microglial activation in vitro (Table 1).
Kowalski et al. demonstrated that flupentixol and
trifluperidol reduced the secretion of TNF-a and
NO by activated microglia,76 and flupentixol, trifluperidol, chlorpromazine and loxapine have been
reported to reduce IL-1b and IL-2 release by activated
microglia.77,78 Until recently, the pharmacological
action of atypical antipsychotics on microglial cells
has not been well understood. Hou et al. demonstrated that olanzapine inhibited NO release from the
activated microglia, while haloperidol and clozapine
did not.79 We recently demonstrated that risperidone
significantly inhibited the IFN-g-activated microgliaderived production of NO and pro-inflammatory
cytokines such as IL-1b, IL-6, and TNF-a in comparison to haloperidol, a typical antipsychotic.80 We furthermore demonstrated the same inhibitory effects
on IFN-g-induced microglial activation by other

Table 1. Effects of antipsychotics on microglial activation

Antipsychotics

Microglia

Activator

Pro-inflammatory cytokines

Nitric oxide

Reference

Flupentixol

Primary culture

LPS

IL-1b and IL-2, TNF-a: Inhibited

Inhibited

Kowalski et al.
(2003, 2004)76,77

LPS

IL-1b and IL-2, TNF-a: Inhibited

Inhibited

Chlorpromazine
Loxapine

Primary culture

LPS
LPS

IL-1b and IL-2: Inhibited

IL-1b and IL-2: Inhibited

Labuzek et al. (2005)78

Haloperidol
Clozapine
Olanzapine

Cell line (N9)

LPS
LPS
LPS

Not inhibited
Not inhibited
Inhibited

Hou et al. (2006)79

Haloperidol
Risperidone

Cell line (6-3)

IFN-g
IFN-g

IL-1b, IL-6 and TNF-a: Inhibited

IL-1b, IL-6 and TNF-a: Inhibited

Slightly inhibited
Inhibited

Kato et al. (2007)80

Quetiapine
Perospirone
Ziprasidone

Cell line (6-3)

IFN-g
IFN-g
IFN-g

TNF-a: Inhibited
TNF-a: Inhibited
TNF-a: Activated

Inhibited
Inhibited
Inhibited

Bian et al. (2008)81

Aripiprazole

Cell line (6-3)

Primary culture

IFN-g
LPS

TNF-a: Inhibited

Inhibited
Inhibited

Kato et al. (2008)82

Spiperone

Cell line (BV-2)

Primary culture

LPS
ATP

IL-1b, TNF-a: Inhibited (mRNA)

Inhibited
Inhibited

Zheng et al. (2008)83

Trifluperidol

ATP, adenyl triphosphate; IFN-g, interferon-g; IL, interleukin; LPS, lipopolysaccharide; TNF, tumor necrosis factor.

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A. Monji et al.

atypical antipsychotics such as perospirone and

quetiapine.81 There have been some reports that suggested a relationship between schizophrenia and
IFN-g, a major immunoactivator in the CNS. The
most important immunological studies in schizophrenia have shown that a shift from T-helper 1
(Th1)-like cellular to Th2-like humoral immune reactivity is the most characteristic common immune
finding and these studies have suggested a blunted
IFN-g signal in schizophrenia.84 Rothermundt et al.,
however, have argued that the reduced IFN-g production in vitro may reflect an increased production in
vivo, because it is found in several autoimmune disorders.85 Furthermore, the serum levels of IL-2 and
IFN-g, and the production of these cytokines from the
peripheral blood mononuclear cells stimulated by
phytohemagglutinin have been reported to be significantly higher in schizophrenia patients than in controls.86 Furthermore, a recent systematic quantitative
review on the inflammatory cytokine alterations in
schizophrenia did not support the Th2 shift hypothesis of schizophrenia.11
Spiperone, a typical antipsychotic, also inhibited
the production of NO and pro-inflammatory cytokines such as IL-1b and TNF-a from activated microglia, while spiperone was neuroprotective, because
the drug reduced microglia-mediated neuroblastoma
cell death in the microglia/neuron co-culture.83

Antipsychotic with dopamine D2 receptor

partial agonism
Aripiprazole is a novel atypical antipsychotic, which
is a high-affinity dopamine D2 receptor partial
agonist. We also demonstrated that aripiprazole significantly inhibited the generation of NO and TNF-a
from IFN-g-activated microglia, while quinpirole,
dopamine D2 full agonist did not.
Our results demonstrated that not only antipsychotics that have dopamine D2 receptor antagonism
but also aripiprazole, a dopamine D2 receptor
partial agonist, have anti-inflammatory effects via
the inhibition of microglial activation.82 Microglia
are known to have some kinds of neurotransmitters
including dopamine D2 receptors,87 but because
second generation drugs have positive effects on
neuronal cell growth and survival by unique signaling pathways,88 the pharmacological basis for their
neuroprotective effect appears not always to be
related directly to the conventional neurotransmitter
receptors.

Psychiatry and Clinical Neurosciences 2009; 63: 257265

Perspective
All of these studies suggest that some antipsychotics
may therefore have a potentially useful therapeutic
effect on patients with schizophrenia by reducing
microglial inflammatory reactions, which may cause
the apoptotic process, the inhibition of neurogenesis,
and the white matter abnormalities in the brains of
patients with schizophrenia. This is consistent with
the evidence showing antipsychotics influence on
slowing the progressive reduction in cortical gray
matter in schizophrenia.72 In contrast, microglia
can secrete neurotrophic factors other than proinflammatory cytokines and free radicals such as
BDNF. A recent study has shown that a7 nicotinic
acetylcholine receptor agonist (a7nAChR) can
modify microglial activation into a neuroprotective
role by suppressing the inflammatory state and
strengthening the protective function.89 These results
are very interesting because some a7nAChR agonists
are known to improve the cognitive dysfunction of
schizophrenia.90 The appropriate control of microglial activation may thus be a promising therapeutic
target for schizophrenia. Pro-inflammatory cytokines
are also known to play important roles in the pathophysiology of depression.91 Etanercept, which is a
soluble TNF-a receptor that prevents TNF-amediated response, has recently been reported to
relieve fatigue and symptoms of depression with psoriasis.92 Immnosuppression or immunomodulatory
drugs may thus be beneficial at least for the treatment
of acute schizophrenia.93

CONCLUSIONS
In many aspects the neuropathology of schizophrenia is closely associated with microglial activation.
We and other researchers have shown the inhibitory
effects of some typical or atypical antipsychotics on
the release of inflammatory cytokines and free radicals from activated microglia. Our microglia hypothesis of schizophrenia (Fig. 1) may shed new light on
the therapeutic strategy for schizophrenia.

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