Schizophrenia Research 176 (2016) 14–22

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Schizophrenia Research

journal homepage: www.elsevier.com/locate/schres

Clinical studies of neuroinflammatory mechanisms in schizophrenia

Crystal C. Watkins a,b,⁎, Sarah Ramsay Andrews b
a
Memory Center in Neuropsychiatry, Sheppard Pratt Health Systems, Baltimore, MD, United States
b
Department of Psychiatry, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, United States

a r t i c l e i n f o a b s t r a c t

Article history: Schizophrenia is a pervasive neurodevelopmental disorder that appears to result from genetic and environmen-
Received 10 April 2014 tal factors. Although the dopamine hypothesis is the driving theory behind the majority of translation research in
Received in revised form 8 June 2015 schizophrenia, emerging evidence suggests that aberrant immune mechanisms in the peripheral and central ner-
Accepted 8 July 2015
vous system influence the etiology of schizophrenia and the pathophysiology of psychotic symptoms that define
Available online 30 July 2015
the illness. The initial interest in inflammatory processes comes from epidemiological data and historical obser-
Keywords:
vations, dating back several decades. A growing body of research on developmental exposure to infection, stress-
Schizophrenia induced inflammatory response, glial cell signaling, structural and functional brain changes and therapeutic trials
Inflammation demonstrates the impact that inflammation has on the onset and progression of schizophrenia. Research in an-
Microglia imal models of psychosis has helped to advance clinical and basic science investigations of the immune mecha-
Glutamate nisms disrupted in schizophrenia. However, they are limited by the inability to recapitulate the human
Stress response experience of hallucinations, delusions and thought disorder that define psychosis. To date, translational studies
Psychosis of inflammatory mechanisms in human subjects have not been reviewed in great detail. Here, we critically re-
view clinical studies that focus on inflammatory mechanisms in schizophrenia. Understanding the
neuroinflammatory mechanisms involved in schizophrenia may be essential in identifying potential therapeutic
targets to minimize the morbidity and mortality of schizophrenia by interrupting disease development.
© 2015 Elsevier B.V. All rights reserved.

1. Introduction Schizophrenia is likely the most researched of the neuropsychiatric

Schizophrenia is a disabling psychiatric disorder that affects an esti-
mated 250 million people across the world at some point in their life
(van Os and Kapur, 2009). Delusions, hallucinations, disorganized
thinking and cognitive impairment are hallmarks of schizophrenia.
Schizophrenia is a disease with no cure and long-term individual, family
and societal costs. Suicide rates of those suffering from schizophrenia
approach 10–15% (Rossler et al., 2005). Significant discoveries related
to early identification, early treatment and stabilization with medica-
tions have led to more extensive research and a better long-term prog-
nosis for schizophrenic patients.
Abbreviations: CNS, central nervous system; COX, cyclooxygenase; CSF, cerebrospinal
fluid; EAAT2, excitatory amino acid transporter 2; GWAS, genome-wide association study;
HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; KYP, kynurenine pathway;
LPS, lipopolysaccharide; MRS, magnetic resonance spectroscopy; MHC, major histocom-
patibility complex; NAC, N-acetylcysteine; iNOS, inducible nitric oxide synthase; NK, nat-
ural killer; NMDA, N-methyl D-aspartate; NSAID, non-steroidal anti-inflammatory agents;
PET, positron emission tomography; Polyl:C, polyriboinosinic–polyribo-cytidylic acid; RA,
rheumatoid arthritis; ROS, reactive oxygen species; SLE, systemic lupus erythematosus;
SNP, single nucleotide polymorphism; TGF, transforming growth factor; Th, T helper;
TNF, tumor necrosis factor; TSPO, translocator protein.
⁎ Corresponding author at: Department of Neuropsychiatry, Sheppard Pratt Health
Systems, Gibson Building, Suite 100, 6501 N. Charles St., Baltimore, MD 21204, United
States.
E-mail address: cwatkins@jhmi.edu (C.C. Watkins).
diseases with an advanced scientific understanding of the genetic, envi-
ronmental, molecular and physiologic contributing factors (Insel, 2011;
Jaaro-Peled et al., 2009a; Muller and Schwarz, 2010; van Os and Kapur,
2009). However, there remains insufficient knowledge regarding the
primary origin and subsequent progression of the disease. This may be
due in part to the complexity of the illness and logistical challenges of
studying psychotic symptoms in human subjects. Given the ability to
manipulate neurotransmitter signals, animal models have been critical
in determining that inflammatory signatures and cytokine signaling
are precursors to psychosis. The collective literature in animal models
appears to mimic the progressive nature of the clinical syndrome of
schizophrenia, with exposure to pathogens in-utero and then develop-
ment of aberrant pathology and clinical/behavioral symptoms emerging
in adolescence or early adulthood. However, animal models have limita-
tions in being able to recapitulate positive and negative symptoms of
psychosis. The need for translational approaches in clinical schizophre-
nia investigations, the difficult nature of experimental design, and the
clinical morbidity and mortality of the disease have generated research
interest in new hypotheses that address the etiological process of
schizophrenia in human subjects, cells and tissue and subsequently
help lay the foundation for new therapies.
Historically, the pathophysiology of schizophrenia has been
linked to abnormal neurodevelopment and deficits in dopamine.
While the dopamine hypothesis has defined schizophrenia for

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 C.C. Watkins, S.R. Andrews / Schizophrenia Research 176 (2016) 14–22 15

many years, a growing number of research investigations and scien-
tific curiosity have developed around the immune system and the
role of neuroinflammation in precipitating psychotic symptoms in
a subset of patients with psychosis (Drexhage et al., 2010; Miller
et al., 2011; Potvin et al., 2008; Upthegrove et al., 2014). These stud-
ies provide a detailed review of the theories and mechanisms that
support a role for inflammation in schizophrenia. Since the 1980s
the immune hypothesis of schizophrenia has emerged as a theory
unified by data from human developmental, molecular imaging
and therapeutic trial techniques. The consensus is that alterations
in the immune system and neuroinflammation lead to progressive
brain changes in schizophrenia (Fudenberg et al., 1983; Stevens,
1983). Epidemiologic, developmental, neuropathological and neu-
roimaging observations have further advanced clinical and neuro-
science investigations in support of neuroinflammatory pathways
in psychiatric illness.
Immune system dysfunction may result in part from prenatal expo-
sure to a maternal infection of cerebral insult from Toxoplasma gondii,
Cytomegalovirus, Chlamydia, influenza or other infectious agents that
generate an immune response (Ellman et al., 2009; Khandaker et al.,
2014b; Smesny et al., 2010). The subsequent cytokine cascade is
thought to alter neuronal development before the illness is clinically
expressed (Chew et al., 2013; Hagberg et al., 2012; Jaaro-Peled et al.,
2009b). More recent developmental studies using schizophrenia pa-
tients and tissues have clarified this initial observation and shown
that the inflammatory response, not necessarily the disease pathogen,
alters the developmental trajectory of neurons (Meyer et al., 2010;
Miller et al., 2011). Immune-related genes have also been linked to ab-
errant immune signaling in schizophrenia (Jia et al., 2010; Stefansson
et al., 2009).
In response to infection, stress-induced inflammation appears
to lead to psychopathological symptoms. In animal behavioral
studies, an increased release of cytokines is suggested to mediate
a cascade that “desensitizes” the immune system. This leads to
changes in cellular proliferation, which further increases proin-
flammatory cytokines downstream. Cytokines are also important
in the immune mechanisms of schizophrenia, as they activate the
kynurenine pathway — an alternate route for tryptophan metabo-
lism that leads to long-term changes in glutamatergic function, tro-
phic support and synaptic function (Fig. 1). Glia cells in the form of
astrocytes and microglia further support the role of the immune
system. Microglia in particular act as cytokine sensors and serve
as the key regulatory cells of the immune system in the central ner-
vous system (CNS). Structural, molecular and functional changes in
microglia were noted in post-mortem schizophrenia patients who
completed suicide (Radewicz et al., 2000; Steiner et al., 2008b,
2011b; Wierzba-Bobrowicz et al., 2005). However, investigations
using immunohistochemical markers have not consistently report-
ed glial cell changes across all studies (Matthews and Harrison,
2011). Inflammatory mediators, through microglia and kynurenine
metabolism, provide a related link to glutamate, dopamine and
downstream reactive oxygen species as markers of oxidative stress
in the pathophysiology of schizophrenia (Flatow et al., 2013;
Kohen and Nyska, 2002; Muller, 2014; Swerdlow et al., 2009).
We conducted a critical review of the literature for articles on
PubMed involving clinical studies and the search terms, schizophrenia
and inflammation. We then assessed the data related to immune mod-
ulation of schizophrenia in either human tissue, cells or patients with
schizophrenia. We selected articles where the primary language was
English and then critically reviewed the multidisciplinary, translational
research in schizophrenia subjects and subjects with non-affective psy-
chosis. We discuss and analyze these investigations and identify poten-
tial therapeutic targets that may mitigate the debilitating effects of the
disease and lead to a better-long term prognosis for patients.

Fig. 1. Neuroinflammatory mechanism involved in schizophrenia and linked through kynurenine pathway (CRP — C-reactive protein; IDO — indoleamine 2,3-dioxygenase; 5-HT — serotonin;
RNS — reactive nitrogen species; ROS — reactive oxygen species).

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16 C.C. Watkins, S.R. Andrews / Schizophrenia Research 176 (2016) 14–22
2. Systemic infections and neurodevelopmental mechanisms of
immune system activation in schizophrenia
2.1. Systemic infections and neurodevelopmental mechanisms
Schizophrenia is thought of as a multifactorial disorder with contri-
butions from the environment, genetics and other pathophysiological
processes that form a cluster of clinical symptoms. Given the strong in-
teractions between genetics and the environment, more research has
focused on the immune system in early exposure to infection as well
as genes that are common in infection and psychosis. The perception
of an infectious cause of schizophrenia emerged from anecdotal
evidence over 150 years ago. Modern epidemiological evidence from
national registries describes a cohort of individuals with genetic vulner-
abilities for immune disorders and psychosis (Eaton et al., 2010;
Severance et al., 2014a, 2014b). Severe infections and autoimmune dis-
orders over a lifetime appeared to confer additive risk for schizophrenia
and schizophrenia spectrum disorders (Benros et al., 2013b; Meyer,
2011). In contrast, parental infection alone did not appear to be a defin-
itive risk factor (Benros et al., 2013a, 2013b). These data suggest that
systemic infections might impact the developing fetal brain, making it
vulnerable to brain illnesses later in life (Ellman et al., 2009).
Epidemiologic research, post-mortem research, and imaging research
in human subjects, consistently support the relationship between the im-
mune system and psychosis, specifically the neurodevelopmental expo-
sure to infection (Brown and Derkits, 2010; Cannon et al., 2002; Meda
et al., 2014; Rapoport et al., 2012). Pregnancy, a period where the mother
is more vulnerable to infections and elevations in proinflammatory
cytokines, may reflect a deviation from the normal immune processing.
During influenza epidemics and heightened infection exposure from the
winter to spring months, pregnant women are at higher risk for giving
birth to offspring that develop schizophrenia (Brown and Derkits, 2010;
Meyer et al., 2010). Respiratory infections (Sorensen et al., 2009; Selten
et al., 2009) and reproductive tract infections (Babulas et al., 2006;
Sorensen et al., 2009) during pregnancy have also been linked to an in-
creased risk for schizophrenia. Other pathogens linked to schizophrenia
include maternal infection with T. gondii (Brown et al., 2005), rubella
(Brown et al., 2000), measles (Torrey et al., 1997), polio (Suvisaari et al.,
1999) and herpes simplex type 2 (Buka et al., 2001a). With the epidemi-
ologic data that infections before birth increase the risk of developing
schizophrenia (Brown and Derkits, 2010; Buka et al., 2001a, 2001b;
Dalman et al., 2008; Gattaz et al., 2004; Yudofsky, 2009), one would also
expect a corresponding increase in antibody titers against the virus. How-
ever, measurements of maternal antibody titers against viruses during
pregnancy have yielded inconsistent results between different studies
(Blomstrom et al., 2012; Brown et al., 2004; Leweke et al., 2004). A
case–control study of 198 individuals born in Sweden from 1975 to
1985 and diagnosed with schizophrenia showed elevated levels of IgG di-
rected at T. gondii. CMV was also elevated as markers of maternal expo-
sure and associated with subsequent development of schizophrenia
(Blomstrom et al., 2012). There were no associations between any of
the infectious agents and other non-affective psychoses. However, epide-
miologic studies are often limited because of their observational nature;
they are unable to show the role of inflammation as a cause or an effect
of schizophrenia.
Most infections do not cross the placenta, with the exception of
parasitic infections like T. gondii. Therefore, damaging effects to the
fetal brain are likely through maternal or fetal responses to infections
through the placenta (Patterson, 2009; Shi et al., 2005). Cognitive and
neurological impairments have been observed after in-utero exposure
to infection and appear to correlate with changes in white matter around
the ventricles, termed periventricular leukomalacia (Dammann and
Leviton, 1997; Favrais et al., 2011; Sorensen et al., 2006; Chew et al.,
2013; Hagberg et al., 2012). The subsequent pro-inflammatory changes
and microglial activation in periventricular leukomalacia seem to act as
mediators of CNS inflammation (Dammann et al., 2008; Leviton and
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Gressens, 2007). During the developmental insult, cytokines such as IL-
8 (Brown et al., 2004) and TNF-alpha (Buka et al., 2001b) appear to cir-
culate at higher blood levels in the maternal blood of individuals later
at risk for psychotic disorders. Even infections in later stages of develop-
ment, particularly the second and third trimesters cause higher IL-8
levels that correlate with structural changes in the progeny with schizo-
phrenia in the left entorhinal cortex and right posterior cingulated
(Ellman et al., 2010; Meyer, 2011). Although promising, specific mater-
nal–fetal expression studies in schizophrenia are limited to these few in-
vestigations. In addition, these retrospective and observational studies
are not able to identify the causal mechanism behind psychotic symp-
toms. More recent, prospective cohort studies show a positive correla-
tion between elevated systemic inflammatory marker interleukin 6 (IL-
6) and C-reactive protein (CRP) in childhood (measured at 9 years of
age) and development of future psychosis and depression in early life
(after age 18) (Khandaker et al., 2014a, 2014b). Childhood atopic disor-
ders such as asthma and eczema were also suggested to increase the
risk of psychotic experiences in adolescence (Khandaker et al., 2013).
Translational approaches in mouse and rat models with lipo-
polysaccharide (LPS) and polyriboinosinic–polyribo-cytidylic acid
(Polyl:C) have also examined the role of chronic versus acute inflamma-
tion in neurodevelopment. The collective literature in animals appears
to mimic the progressive nature of the clinical syndrome of schizophre-
nia. Although exposure to numerous pathogens occurs in-utero, the ab-
errant pathology and clinical/behavioral symptoms are not evident
until adolescence or early adulthood.
2.2. Genetic polymorphisms
In addition to the environmental contribution from prenatal infec-
tion, immune related genes and alterations in the immune response
have been found in schizophrenia patients (Consortium, 2014; Jia
et al., 2010; Schwarcz et al., 2001). These and other studies have looked
at the collective involvement of inflammatory genes in schizophrenia
and the details and number of genes involved are beyond the scope of
our review. Genome-wide association studies allow for the identifica-
tion of genetic polymorphisms or divergent genes and altered immune
signaling that may confer a genetic susceptibility to infection (Drago
et al., 2014). Genetic studies from large, multiple cohorts suggest that
the polymorphisms vulnerable to schizophrenia are positioned on dif-
ferent gene loci located on chromosome 6p22 (Drago et al., 2014;
Purcell et al., 2009; Stefansson et al., 2009) (Consortium, 2014; Muller,
2014). Several immune-related genes share this region. The most signif-
icant gene associations were with HLA complex genes that moderate
the inflammatory response (Fellerhoff et al., 2007), histone genes that
focus on antimicrobial defense (Kawasaki and Iwamuro, 2008) and his-
tone proteins potentially involved in DNA repair and methylation (Costa
et al., 2009; Kundakovic et al., 2007). A meta-analysis complied many of
the genetic studies to date and was able to pinpoint specific variants of
immune-related genes in schizophrenia (Ripke et al., 2013). However,
the specific polymorphisms were expressed in other psychiatric disor-
ders and were not exclusive to psychosis or schizophrenia (Ripke
et al., 2013; Consortium, 2014).
Some suggest that the discrepancy is because a genetic disposition
for immune activation in mental illness may only be expressed in a
subgroup of people (Pathmanandavel et al., 2013). Others argue that ex-
pression of inflammatory genes may be brain region specific or have a
temporal relationship to a specific brain insult. One microarray and
RNA sequence study shows abnormal immune/inflammatory responses
limited to the hippocampus (Hwang et al., 2013). Another study looking
at mRNA expression of inflammatory genes in a cohort of schizophrenia
subjects showed a difference in psychotic patients older 40 years of age
compared to those under 40 (Tang et al., 2012). The specific location of
gene expression may be directly related to the long-term neurocognitive
deficits associated with schizophrenia. There may also be a temporal
 C.C. Watkins, S.R. Andrews / Schizophrenia Research 176 (2016) 14–22
relationship, with immune genes more prominently expressed with du-
ration of the illness and/or age.
3. Immune response and inflammatory mediators
3.1. Innate immune pathways, cytokine signaling and downstream
inflammation
Although much of the developmental literature stems from models
of peripheral infection acting directly to contribute to neuroinflamma-
tion, many initially doubted the theory because the blood–brain barrier
protects the CNS from systemic infection. More recent research has
been able to distinguish immune signals in the innate immune system,
predominated by monocytes and macrophages that defend the blood–
brain barrier, and the adaptive immune system, which is comprised of
cytokines and chemokine signals secreted from these cells (Miller
et al., 2011; Muller, 2014; Upthegrove et al., 2014). These cytokines
and their receptors appear to be fundamental to fetal neuronal growth,
migration and survival (Bakhiet et al., 2002; Mehler and Kessler, 1998;
Meyer et al., 2010; Mousa et al., 1999). In the adult brain, in addition
to their immune function, cytokines are signaling molecules within
the brain and important in astrocyte and glial cell communication
(Muller, 2014). The individual pro- and anti-inflammatory markers in-
volved in schizophrenia and inflammation are reviewed elsewhere in
detail (Tomasik et al., in press). Previous studies have shown heteroge-
neous results with peripheral cytokine measures, in part due to con-
founding variables including medications and duration of illness.
However, a number of studies in both chronic and first episode schizo-
phrenia show increased expression of interleukin (IL)-1beta, IL-6, IL-8,
tumor necrosis factor (TNF) and C-reactive protein in both peripheral
blood and cerebral spinal fluid (CSF) (Hayes et al., 2014; Kunz et al.,
2011; Miller et al., 2011; Schwieler et al., 2014). Although many im-
mune modulators have been studied, the most consistent research iden-
tifies elevated levels of IL-6 in both the cerebral spinal fluid (CSF) and
serum of individuals with schizophrenia. In particular, drug-naïve, first
episode schizophrenia patients had elevated IL-6, IL-10 and TNF-α at
baseline. Treatment with risperidone over time leads to and repeated
measurements showed a decrease in all three cytokines and IL-4. Fur-
thermore, there was no difference in cytokine levels in healthy controls
compared to the post-treatment group (Noto et al., 2014). This is of in-
terest because IL-6 is directly secreted from monocytes and is a major
component of the adaptive immune system (Hayes et al., 2014; Miller
et al., 2011; Muller, 2014). The change after treatment suggests that in-
flammatory cytokines are related to state changes in schizophrenia.
Translational techniques that combine peripheral blood and CSF mea-
surements with gene microarray date and longitudinal measurements
will be necessary in order to further advance the field. We may also be
able to gain more information from other potential state markers of in-
flammation, like methylation of phosphatase SHP-1, a key negative reg-
ulator of the inflammatory process. SHP-1 is easily measured in
peripheral blood monocytes and appears to be impaired in schizophre-
nia (Pesce et al., 2014).
3.2. Oxidative stress and reactive oxygen species
In addition to activating cytokines, induction of the immune re-
sponse and activation of the inflammatory components appear to
have downstream effects on glutamate, oxidative stress, and the ar-
achidonic acid pathway (Muller, 2014; Muller and Schwarz, 2010).
Oxidative stress is defined as the “imbalance between the systemic
manifestation of reactive oxygen species and the body's ability to
eliminate the reactive oxygen species (ROS)” (Kohen and Nyska,
2002; Muller and Schwarz, 2010). Oxidative stress may also affect
lipid and glucose metabolism in psychosis (Aleksovska et al., 2014).
The innate immune system generates ROS and reactive nitrogen
species (RNS) to assist with the destruction of foreign pathogens
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17
(Nathan and Shiloh, 2000). Activation of pro-inflammatory cyto-
kines such as IL-6 or TNF-alpha might induce the activation of apo-
ptosis through microglial activation and subsequent production of
reactive oxygen species (ROS) and increase reactive nitrogen species
(Fig. 2). An additional pathway that promotes oxidative stress in
schizophrenia is the activation of NMDA receptor through glutamate.
Glutamate is actively taken up into astrocytes and is converted into
glutamine. Alterations in glutamine increase calcium influx into neu-
rons, which may contribute to excitotoxicity, NMDA antagonism in
schizophrenia and altered neurotransmission. The imbalance in the
glutamatergic neurotransmission leads to further production of
ROS and RNS, which leads to nitrosative damage to DNA, proteins
and lipids, in a situation where oxidative defenses are already
vulnerable.
The anti-oxidant defense system appears to be altered in schizophre-
nia (Flatow et al., 2013). A recent meta-analysis demonstrated decreased
serum and plasma antioxidant markers in first episode schizophrenia pa-
tients that increased longitudinally with anti-psychotic treatment (Flatow
et al., 2013). Another study showed a reduction in superoxide dismutase
enzyme (SOD-1) in the serum and CSF of individuals experiencing their
first episode of schizophrenia (Coughlin et al., 2012). Increasing evi-
dence from the fields of neurophysiology and neuropathology has un-
covered the role of polyunsaturated fatty acids (PUFA) in protecting
neuronal cells from oxidative damage, controlling inflammation, regu-
lating neurogenesis, and preserving neuronal function (Hashimoto
et al., 2014). Based on a recent review of oxidative stress and schizo-
phrenia, understanding this relationship through both human and ani-
mal studies could be the key to treatment options for patients with
schizophrenia (Emiliani et al., 2014).
3.3. COX inhibition and anti-inflammatory mechanisms
Cyclooxygenase-2 (COX-2), an influential regulator of pain and in-
flammation, is the key enzyme in the arachidonic acid pathway respon-
sive to cytokines. Inflammatory cytokines such as IL-1 beta and tumor
necrosis factor (TNF)-alpha have been shown to enhance expression
of COX-2 mRNA (Muller and Schwarz, 2010; Sommer et al., 2013).
Therefore, inhibition of COX-2 is important in dampening the cytokine
response and minimizing inflammation.
Like the inflammatory cytokines, COX is also influenced by the
kynurenine pathway. Inhibition of COX-2 by celecoxib decreases levels
of kynurenic acid, while inhibition of COX-1 increases levels of
kynurenic acid (Muller and Schwarz, 2010; Schwieler et al., 2014).
Expanding on this anti-inflammatory mechanism, double-blind ran-
domized trials in acute schizophrenia reported symptom improvement
when risperidone was augmented with celecoxib (Akhondzadeh et al.,
2007; Muller et al., 2004, 2010). Although the results have not been rep-
licated in subsequent studies, Muller and colleagues concluded that the
duration of schizophrenia impacts the timing and effectiveness of COX-
2 inhibitors (Muller et al., 2004). Prospective, randomized, double-blind
clinical trials of first episode schizophrenia (Fond et al., 2013) and
chronic schizophrenia (Akhondzadeh et al., 2007), demonstrated that
augmentation of atypical antipsychotics with celecoxib had a therapeu-
tic effect. Individuals with long-standing psychotic symptoms did not
appear to respond to the COX-2 inhibitor. As we mentioned with cyto-
kine expression earlier, there also appears to be an age effect in arachi-
donic acid related inflammatory pathways with PTGS-1 (a measure of
COX-1) and PTGS-2 (a measure of COX-2) decreased in older subjects
with schizophrenia compared to those younger than 40 (Tang et al.,
2012). Therefore, age may be a factor in therapeutic response. While
promising, interpretation of the celecoxib trials is limited due to few
studies on mono-treatment with celecoxib and the brief duration of
these trials.
The benefits of anti-inflammatory therapy are not limited to
celecoxib. Nonsteroidal anti-inflammatory drugs (NSAIDs), reviewed
in a recent meta-analysis, added to either risperidone or olanzapine
18 C.C. Watkins, S.R. Andrews / Schizophrenia Research 176 (2016) 14–22

Fig. 2. Activation of pro-inflammatory cytokines such as IL-6 or TNF-alpha might induce activation of apoptosis through microglial activation and subsequent production of reactive oxygen
species (ROS) and increase reactive nitrogen species. An additional pathway that promotes oxidative stress in schizophrenia is the activation of NMDA receptor through glutamate. Glu-
tamate is actively taken up into astrocytes and is converted into glutamine. Alterations in glutamine increase calcium influx into neurons, which may contribute to excitotoxicity, NMDA
antagonism in schizophrenia and altered neurotransmission. The imbalance in the glutamatergic neurotransmission leads to further production of ROS and RNS, which leads to damage to
DNA, proteins and lipids, in a situation where oxidative defenses are already vulnerable. These differences are the following: CRP-C — reactive protein; IDO — indoleamine 2,3-
dioxygenase; 5-HT — serotonin; RNS — reactive nitrogen species; ROS — reactive oxygen species; and GLU — glutamate.

resulted in a decline in psychotic symptomatology in patients with
schizophrenia (Meyer, 2011; Sommer et al., 2013). Adjuvant aspirin
therapy reduces the symptoms of schizophrenia measured by the Posi-
tive and Negative Symptoms Score (PANSS) scale, with a more pro-
nounced reduction in those with the more altered immune function
(Laan et al., 2010). Compared to antipsychotic monotherapy,
minocycline (a broad-spectrum antibiotic), when added to an antipsy-
chotic, showed a significant reduction in symptoms and additive cogni-
tive benefit in double-blind, randomized trials of patients with recent
onset schizophrenia (Levkovitz et al., 2010). Several studies have also
reported that antipsychotic drugs themselves counteract the inflamma-
tory effects of cytokine networks, although the exact mechanism is not
known (Kroken et al., 2014; Sommer et al., 2013).
4. Structural and functional mediators of neuroinflammation
4.1. Glial signaling and the immune response
Postmortem brain studies of schizophrenia were some of the first to
demonstrate preservation of the number of neurons with diminished
glia cell numbers and altered morphology (Monji et al., 2009). Further
research has led disagreements about which glial-subtype is most im-
portant in schizophrenia and the neuroinflammatory hypothesis.
Changes in white matter intensities have been successively reported
in schizophrenia patients and post-mortem studies and appear to be
linked to oligodendrocyte gene polymorphism, resulting in a decrease
of the overall number of oligodendrocytes (Bernstein et al., 2012;
Hercher et al., 2014). More recent studies have examined the comple-
ment system and increased risk for schizophrenia in adult offspring
by focusing on complement regulatory proteins in glial signaling
(Severance et al., 2014a, 2014b; Mayilyan et al., 2006). However, most
studies have focused on the role of astrocytes and microglia in schizo-
phrenia because of their roles in glutamate metabolism and cytokine
signaling, respectively (Le Hellard et al., 2008).

Glia cells, the connecting tissue in the brain, also appear to bridge ge-
netic susceptibility with inflammation and neurotransmitter signaling
in schizophrenia (Steiner et al., 2011a). In addition to changes in im-
mune cell activation and response, there is accumulating evidence of
abnormalities in the homeostatic support and protection in the brain
that is preserved by glia cells (oligodendrocytes, astrocytes and microg-
lia) in individuals with schizophrenia. Oligodendrocytes produce
myelin and provide insulation and support for neurons. Astrocytes are
star-shaped cells that provide biochemical support to neurons, secrete
IL-10 and inhibit the production of IL-12. Microglia are transformed pe-
ripheral macrophages in the CNS that sense inflammation and secrete
IL-12. The anatomic and functional changes of glial cells have emerged
as a mechanism of interest in multiple psychiatric disorders (Bernstein
et al., 2009; Monji et al., 2009; Muller, 2014; Watkins et al., 2014).
4.2. Astrocytes and microglia
Replication of both astrocyte and microglia pathology using immu-
nohistochemical methods in post-mortem brains of schizophrenic
patients has led to inconsistent results and conclusions. This is often ex-
plained by age-related brain changes, differences in tissue processing
and differences in immunostaining technique. However, the consensus
is that glial damage is suspected given the increase in astrocyte concen-
tration in patients with schizophrenia. Schizophrenia patients also ap-
pear to have hyper-functioning astrocytes, measured by increases in
the astrocyte marker S100B and glial cell activation (Rothermundt
et al., 2007). The strongest supporting evidence comes from the modu-
lation of glutamate metabolism by astrocytes (Steiner et al., 2008a,
2011b). Defective astrocyte signaling is thought to result in low levels

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 C.C. Watkins, S.R. Andrews / Schizophrenia Research 176 (2016) 14–22
of glutamate and increased NMDA receptor activity. We will discuss the
role of glutamate in glial cells in detail in the next section.
Microglia, upon sensing a change in the brain environment, undergo
a conformational change and become “activated.” When activated they
produce pro-inflammatory cytokines and express protein markers.
Several post-mortem investigations of completed suicides by schizophrenic
patients show increased microglial activation (Matthews and Harrison,
2011; Radewicz et al., 2000; Wierzba-Bobrowicz et al., 2005; Bernstein
et al., 2012). There are also signs of altered expression of microglial protein
markers in peripheral blood, monocytes and cultured microglia from
schizophrenic patients (Zheng et al., 2008). Recently one group affiliated
with the Sydney Tissue Resource Center discovered increased expression
of cytokine mRNA levels in the post-mortem brains of people with
schizophrenia that corresponded with alterations in microglial density
(Fillman et al., 2013). In contrast, other studies did not observe a significant
difference in the number or appearance of microglia (Arnold et al., 1996;
Steiner et al., 2008b; Takano et al., 2010).
Antipsychotic drugs have been shown to inhibit microglial activa-
tion, astrocyte signaling and cytokine production, with the majority of
studies in rodent models (Zheng et al., 2008) and a limited few in
human cultured cells (Chew et al., 2013; Monji et al., 2009; Radomska
et al., 2013) or postmortem studies (Kim et al., 2012) (Busse et al.,
2012). Some propose that the activation of microglia leads to increased
nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and
inducible (i)-NOS expression that contributes to increased oxidative
stress. The acute on chronic activation damages the supporting cells
and may contribute to the clinical symptoms of schizophrenia. Taken
together, astrocytes and glia appear to have both complementary and
contradictory roles in the neuroinflammatory response. Further re-
search into the mechanism of glial dysfunction and inflammation may
give rise to new therapeutic approaches.
4.3. Downstream effects of inflammation on neuro-circuitry
Like astrocytes, microglia have a functional role in neurotransmitter
signaling through cytokine-induced mechanisms that ultimately affect
neurogenesis, glutamate production and excitotoxicity in the brain
(Muller, 2014; Steiner et al., 2011a). Microglia appear to play a
major role in mood and serotonin metabolism through the enzyme
indoleamine 2,3-dioxygenase (IDO) in the kynurenine pathway (KYP).
Schizophrenia patients tend to have co-morbid depression symptoms
that may be related to changes in serotonin (Steiner et al., 2011b).
Working through common enzymes and cytokine signals in the KYP, as-
trocytes are responsible for the release and re-uptake of glutamate. Clin-
ical observations using ketamine and phencyclidine treatment show
that alterations in glutamate receptors and the ultimate antagonism of
NMDA receptors produce a constellation of symptoms comparable to
the psychotic, behavioral and cognitive disturbances in schizophrenia
(Coyle, 2006).
Glutamate is also linked to schizophrenia and neuroinflammation
through microglia and the kynurenine–tryptophan signaling mecha-
nism (Fig. 2). Glutamatergic hypofunction may proceed or be the result
of dopaminergic dysfunction, in the limbic system and frontal cortex of
the brain. Dopamine has long been accepted as one of the main neuro-
transmitters disturbed in schizophrenia. Inflammatory mediators,
through microglia and kynurenine metabolism, provide a related link
to glutamate, dopamine and downstream reactive oxygen species as
markers of oxidative stress in the pathophysiology of schizophrenia
(Erhardt et al., 2001; Muller, 2014; Sathyasaikumar et al., 2010;
Schwarcz et al., 2001; Swerdlow et al., 2009).
Genetic defects in the glutamate receptor gene GRM3 are also relat-
ed to schizophrenia-type symptoms (Bustillo et al., 2014). Immunohis-
tochemical data confirms GRM3 localization to astrocytes (Spangaro
et al., 2012). Molecular biology studies also show that astrocytes help
regulate glutamate transport that involves the excitatory amino acid
transporter 2 (EAAT2) (Huerta et al., 2006). In summary, glia appear
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19
to be important cells in glutamate metabolism, the KYP and the immune
system.
5. Structural and functional brain imaging and inflammation
5.1. Magnetic resonance imaging
Molecular imaging methods that study glia as markers of neuroin-
flammation may lend insight into the pathogenesis of schizophrenia.
Structural imaging studies using magnetic resonance imaging (MRI)
demonstrate reduced CNS brain volume in recent onset schizophrenia
(Dieset et al., 2015; Steen et al., 2006). Chronic disease also shows a pro-
gressive deterioration in brain volume that is related to more clinically
severe disease symptoms (Gogtay et al., 2008; Steen et al., 2006).
Changes in the cellular architecture of the brain are associated with in-
creased levels of IL-1 and IL-6 in acute exacerbation episodes of schizo-
phrenia (Garver et al., 2003; Meisenzahl et al., 2001). Other studies of
the Edinburgh High Risk cohort showed reduction in brain volume in
the temporal gyrus with disease progression that was apparent prior
to the worsening of clinical symptoms (Chakos et al., 2005; Job et al.,
2005, 2006). Diffusion tensor imaging (DTI), a newer MRI technique,
uses water and other diffusion patterns to map to understand brain
structure and function at the microscopic level. A recent study com-
bined DTI and measurements of IL-6 and C-reactive protein in patients
with early psychosis. IL-6 levels were inversely correlated with func-
tional anisotropy (an estimate of fiber density, axonal diameter, and
myelination in white matter) and positively correlated with radial diffu-
sivity (Prasad et al., 2014). C-reactive protein also showed a similar
pattern in psychosis compared to healthy controls. These results suggest
a vulnerability of selected neural pathways to immune signals in
schizophrenia.
5.2. Positron emission tomography and spectroscopy studies
When microglia are activated, they express an 18-kDa protein, TSPO.
Positron emission tomography studies have used TSPO ligands as
markers for neuroinflammation in psychiatric disorders to estimate
the rate of microglia activity (Watkins et al., 2014). The first generation
TSPO ligand, PK1195 showed increased expression of TSPO in the hippo-
campus of schizophrenia patients (Doorduin et al., 2009). Second gener-
ation TSPO ligands like 11C-PBR28, 11C[DAA1106], [(18)F]-FEPPA and
11
C[DPA-713] are being studied in both first episode and chronic schizo-
phrenia (Kreisl et al., 2012) {Sawa et al., unpublished data}. In chronic
schizophrenia, 11C[DAA1106] PET showed no significant difference be-
tween binding in normal controls (Takano et al., 2010). However, partic-
ipants with schizophrenia and a predominance of positive symptoms did
show increased binding. Another PET ligand, [(18)F]-FEPPA examined
white and gray matter regional binding in patients with active psychosis.
This study failed to show a significant difference between symptomatic
patients and healthy controls (Kenk et al., 2014). However, the partici-
pants were actively taking medications. Therefore, either the change in
microglia occurs earlier in the process and/or antipsychotic treatment
may have negated any significant difference between the groups.
Magnetic resonance spectroscopy (MRS) is another imaging modal-
ity that is able to look at the underlying brain chemistry related to in-
flammation. 13C-MRS performed using a 1.5 Tesla magnetic resonance
scanner was able to demonstrate abnormalities in cerebral I-13C glu-
cose, the principal nutrient for glia along with blunted glial metabolism
(Chang et al., 2007). With assistance from the newer 3-Tesla and 7-Tesla
scanners, proton magnetic resonance spectroscopy (1H MRS) and posi-
tron emission tomography investigations, researchers now have the
ability to indirectly measure glutamate by quantitating levels of gluta-
thione and glycine, as markers of neuroinflammation (Bustillo et al.,
2014; Poels et al., 2013). (1H)-MRS was used to measure glutamate,
GABA, and NAAG levels in the anterior cingulate (AC) and centrum
semiovale (CSO) regions (Rowland et al., 2012). Younger schizophrenia
20 C.C. Watkins, S.R. Andrews / Schizophrenia Research 176 (2016) 14–22
subjects had higher NAAG in the CSO when compared with younger
control subjects. Older groups had the reverse finding. Independent of
age, glutamate was reduced in the schizophrenia group. In another
(1H)-MRS study, schizophrenic patients showed increased glutamine
and glutamine to glutamate ratios, but no changes in glutamate levels
in the brain (Bustillo et al., 2014). A recent study using the 7-T (1H)-
MRS was able to non-invasively distinguish glutamate from GABA in
the brain. The group showed decreased GABA/Cr ratios in the prefrontal
cortex in schizophrenia as compared to healthy controls, with GABA/Cr
ratios inversely correlated with cognitive functioning in the patients.
They did not observe any significant change in the GABA/Cr ratio, gluta-
mate, NAA, creatine, or choline in the parieto-occipital cortex region
when patients were compared to controls.
Another study looked at human subjects' in vivo, postmortem brain
and mouse models (Stan et al., 2014). The data demonstrated signifi-
cantly lower glutamate levels in the hippocampus in patients, which
also correlated with lower GluN1 protein levels selectively in the den-
tate gyrus (DG) in postmortem brains. Interestingly, targeted deletion
of the GRIN1 in the mouse model also confirmed a region specific de-
crease in the glutamate concentrations in the whole hippocampus
(Stan et al., 2014). More translation studies like these will be needed
to fully understand neurotransmitter signaling in schizophrenia. Emerg-
ing investigations may provide potential translational techniques to
look at the relationships between brain architecture, brain chemistry
and the inflammatory pathways involved in schizophrenia.
6. Conclusion
The immune system appears to be important in schizophrenia at
multiple-neurobiological levels. The study of inflammatory mechanisms
in psychosis has evolved over the past decades, but further investigations
directed at clinical models and cell cultures from human subjects are
needed. Translational approaches that combine epidemiology, genetics,
oxidative stress, glutamatergic transmission and clinical treatment have
advanced our understanding of the complex neuroinflammatory media-
tors involved in the onset and progress of schizophrenia. The current re-
search supports neurodevelopment, oxidative stress and glial pathology
as relevant immune mechanisms and important targets for therapeutic
intervention in schizophrenia. Still, little is known about the temporal re-
lationship between inflammatory changes and onset of illness. Some of
the research in human subjects still shows heterogeneous results or no
difference between schizophrenia patients and controls. The validity
and reliability of these studies are limited by co-morbid factors like
smoking, cannabis use, medication effects and life stressors, all of which
are difficult to regulate in a longitudinal clinical study of psychosis. With
ubiquitous confounds like stress and inflammation, it is difficult to identi-
fy a causal relationship between the initial infection and other mediating
effects. There may be another affiliated mechanism in schizophrenia that
distinguishes the “prodromal phase” and general psychosis from clinical
schizophrenia, which has yet to be identified. Advances in schizophrenia
will come at the intersection of techniques that combine a specific pheno-
type of schizophrenia, control for gene polymorphisms, measure periph-
eral markers, incorporated cell culture and/or utilize molecular imaging.
Given that further studies are needed to interpret the role of neuroinflam-
mation in schizophrenia, research will have to continue to expand across
multiple disciplines and preclinical and clinical modes. Even with incor-
poration of diverse experimental approaches, targeted therapeutic ap-
proaches will be needed at early stages of development in order to
ultimately manage schizophrenia.
Funding source
Dr. Watkins' research is supported by the Mosaic Initiative Award from the Johns Hop-
kins University, a faculty development grant for early career academic physicians. She is
also funded by the Women's Hospital Foundation from a grant through Neuropsychiatry
at Sheppard Pratt.
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Contribution statement
Both Dr. Watkins and Dr. Andrews contributed to this manuscript. Dr. Watkins con-
tributed to the conception and design, interpretation of data, drafting and revising the ar-
ticle and funding for the project. Dr. Andrews contributed to the data collection, writing
the article and revision of the manuscript for publication.
Conflict of interest
We have no conflicts of interest to disclose.
Acknowledgments
This work was supported by the Johns Hopkins University Mosaic Initiative Award
and a Sheppard Pratt Neuropsychiatry grant from the Women's Hospital Foundation
(CCW).
References
Akhondzadeh, S., Tabatabaee, M., Amini, H., Ahmadi Abhari, S.A., Abbasi, S.H., Behnam, B., 2007.
Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-
controlled trial. Schizophr Res. 90 (1-3), 179–185.
Aleksovska, K., Leoncini, E., Bonassi, S., Cesario, A., Boccia, S., Frustaci, A., 2014. Systematic review
and meta-analysis of circulating S100B blood levels in schizophrenia. PLoS One 9 (9),
e106342.
Arnold, S.E., Franz, B.R., Trojanowski, J.Q., Moberg, P.J., Gur, R.E., 1996. Glial fibrillary acidic
protein-immunoreactive astrocytosis in elderly patients with schizophrenia and dementia.
Acta Neuropathol. 91 (3), 269–277.
Babulas, V., Factor-Litvak, P., Goetz, R., Schaefer, C.A., Brown, A.S., 2006. Prenatal exposure to ma-
ternal genital and reproductive infections and adult schizophrenia. Am. J. Psychiatry 163
(5), 927–929.
Bakhiet, M., Mousa, A., Seiger, A., Andersson, J., 2002. Constitutive and inflammatory induction
of alpha and beta chemokines in human first trimester forebrain astrocytes and neurons.
Mol. Immunol. 38 (12–13), 921–929.
Benros, M.E., Laursen, T.M., Dalton, S.O., Nordentoft, M., Mortensen, P.B., 2013a. The risk of
schizophrenia and child psychiatric disorders in offspring of mothers with lung cancer
and other types of cancer: a Danish nationwide register study. PLoS One 8 (11), e79031.
Benros, M.E., Pedersen, M.G., Rasmussen, H., Eaton, W.W., Nordentoft, M., Mortensen, P.B.,
2013b. A nationwide study on the risk of autoimmune diseases in individuals with a per-
sonal or a family history of schizophrenia and related psychosis. Am. J. Psychiatry 171
(2), 218–226.
Bernstein, H.G., Steiner, J., Bogerts, B., 2009. Glial cells in schizophrenia: pathophysiological sig-
nificance and possible consequences for therapy. Expert. Rev. Neurother. 9 (7), 1059–1071.
Bernstein, H.G., Smalla, K.H., Durrschmidt, D., Keilhoff, G., Dobrowolny, H., Steiner, J., et al., 2012.
Increased density of prohibitin-immunoreactive oligodendrocytes in the dorsolateral pre-
frontal white matter of subjects with schizophrenia suggests extraneuronal roles for the
protein in the disease. Neuromol. Med. 14 (4), 270–280.
Blomstrom, A., Karlsson, H., Wicks, S., Yang, S., Yolken, R.H., Dalman, C., 2012. Maternal antibod-
ies to infectious agents and risk for non-affective psychoses in the offspring — a matched
case–control study. Schizophr. Res. 140 (1–3), 25–30.
Brown, A.S., Derkits, E.J., 2010. Prenatal infection and schizophrenia: a review of epidemiologic
and translational studies. Am. J. Psychiatry 167 (3), 261–280.
Brown, A.S., Cohen, P., Greenwald, S., Susser, E., 2000. Nonaffective psychosis after prenatal ex-
posure to rubella. Am. J. Psychiatry 157 (3), 438–443.
Brown, A.S., Hooton, J., Schaefer, C.A., Zhang, H., Petkova, E., Babulas, V., et al., 2004. Elevated ma-
ternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am. J. Psychiatry 161
(5), 889–895.
Brown, A.S., Schaefer, C.A., Quesenberry Jr., C.P., Liu, L., Babulas, V.P., Susser, E.S., 2005. Maternal
exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am. J. Psychiatry
162 (4), 767–773.
Buka, S.L., Tsuang, M.T., Torrey, E.F., Klebanoff, M.A., Bernstein, D., Yolken, R.H., 2001a. Maternal
infections and subsequent psychosis among offspring. Arch. Gen. Psychiatry 58 (11),
1032–1037.
Buka, S.L., Tsuang, M.T., Torrey, E.F., Klebanoff, M.A., Wagner, R.L., Yolken, R.H., 2001b. Maternal cy-
tokine levels during pregnancy and adult psychosis. Brain Behav. Immun. 15 (4), 411–420.
Busse, S., Busse, M., Schiltz, K., Bielau, H., Gos, T., Brisch, R., et al., 2012. Different distribution pat-
terns of lymphocytes and microglia in the hippocampus of patients with residual versus
paranoid schizophrenia: further evidence for disease course-related immune alterations?
Brain Behav. Immun. 26 (8), 1273–1279.
Bustillo, J.R., Chen, H., Jones, T., Lemke, N., Abbott, C., Qualls, C., et al., 2014. Increased glutamine
in patients undergoing long-term treatment for schizophrenia: a proton magnetic reso-
nance spectroscopy study at 3 T. JAMA Psychiatry 71 (3), 265–272.
Cannon, M., Jones, P.B., Murray, R.M., 2002. Obstetric complications and schizophrenia: histori-
cal and meta-analytic review. Am. J. Psychiatry 159 (7), 1080–1092.
Chakos, M.H., Schobel, S.A., Gu, H., Gerig, G., Bradford, D., Charles, C., et al., 2005. Duration of ill-
ness and treatment effects on hippocampal volume in male patients with schizophrenia. Br.
J. Psychiatry 186, 26–31.
Chang, L., Friedman, J., Ernst, T., Zhong, K., Tsopelas, N.D., Davis, K., 2007. Brain metabolite abnor-
malities in the white matter of elderly schizophrenic subjects: implication for glial dysfunc-
tion. Biol. Psychiatry 62 (12), 1396–1404.
Chew, L.J., Fusar-Poli, P., Schmitz, T., 2013. Oligodendroglial alterations and the role of microglia
in white matter injury: relevance to schizophrenia. Dev. Neurosci. 35 (2–3), 102–129.
Consortium, S. W. o. t. P. G., 2014. Biological insights from 108 schizophrenia-associated genetic
loci. Nature 511 (7510), 421–427.
Costa, E., Chen, Y., Dong, E., Grayson, D.R., Kundakovic, M., Maloku, E., et al., 2009. GABAergic
promoter hypermethylation as a model to study the neurochemistry of schizophrenia vul-
nerability. Expert. Rev. Neurother. 9 (1), 87–98.
Coughlin, J.M., Ishizuka, K., Kano, S.I., Edwards, J.A., Seifuddin, F.T., Shimano, M.A., et al., 2012.
Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of pa-
tients with recent-onset schizophrenia. Mol. Psychiatry 18 (1), 10–11.
 C.C. Watkins, S.R. Andrews / Schizophrenia Research 176 (2016) 14–22
Coyle, J.T., 2006. NMDA receptor and schizophrenia: a brief history. Schizophr. Bull. 38 (5),
920–926.
Dalman, C., Allebeck, P., Gunnell, D., Harrison, G., Kristensson, K., Lewis, G., et al., 2008. Infections
in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of
more than one million Swedish subjects. Am. J. Psychiatry 165 (1), 59–65.
Dammann, O., Leviton, A., 1997. Maternal intrauterine infection, cytokines, and brain damage in
the preterm newborn. Pediatr. Res. 42 (1), 1–8.
Dammann, O., Bueter, W., Leviton, A., Gressens, P., Dammann, C.E., 2008. Neuregulin-1: a poten-
tial endogenous protector in perinatal brain white matter damage. Neonatology 93 (3),
182–187.
Dieset, I., Haukvik, U.K., Melle, I., Rossberg, J.I., Ueland, T., Hope, S., et al., 2015. Association be-
tween altered brain morphology and elevated peripheral endothelial markers — implica-
tions for psychotic disorders. Schizophr. Res. 161 (2–3), 222–228.
Doorduin, J., de Vries, E.F., Willemsen, A.T., de Groot, J.C., Dierckx, R.A., Klein, H.C., 2009. Neuro-
inflammation in schizophrenia-related psychosis: a PET study. J. Nucl. Med. 50 (11),
1801–1807.
Drago, A., Giegling, I., Schafer, M., Hartmann, A.M., Konte, B., Friedl, M., et al., 2014. Genome-
wide association study supports the role of the immunological system and of the
neurodevelopmental processes in response to haloperidol treatment. Pharmacogenet. Ge-
nomics 24 (6), 314–319.
Drexhage, R.C., Knijff, E.M., Padmos, R.C., Heul-Nieuwenhuijzen, L.v.d., Beumer, W., Versnel,
M.A., et al., 2010. The mononuclear phagocyte system and its cytokine inflammatory net-
works in schizophrenia and bipolar disorder. Expert. Rev. Neurother. 10 (1), 59–76.
Eaton, W.W., Pedersen, M.G., Atladottir, H.O., Gregory, P.E., Rose, N.R., Mortensen, P.B., 2010. The
prevalence of 30 ICD-10 autoimmune diseases in Denmark. Immunol. Res. 47 (1–3),
228–231.
Ellman, L.M., Yolken, R.H., Buka, S.L., Torrey, E.F., Cannon, T.D., 2009. Cognitive functioning prior
to the onset of psychosis: the role of fetal exposure to serologically determined influenza
infection. Biol. Psychiatry 65 (12), 1040–1047.
Ellman, L.M., Deicken, R.F., Vinogradov, S., Kremen, W.S., Poole, J.H., Kern, D.M., et al., 2010.
Structural brain alterations in schizophrenia following fetal exposure to the inflammatory
cytokine interleukin-8. Schizophr. Res. 121 (1–3), 46–54.
Emiliani, F.E., Sedlak, T.W., Sawa, A., 2014. Oxidative stress and schizophrenia: recent break-
throughs from an old story. Curr. Opin. Psychiatry 27 (3), 185–190.
Erhardt, S., Blennow, K., Nordin, C., Skogh, E., Lindstrom, L.H., Engberg, G., 2001. Kynurenic acid
levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci. Lett.
313 (1–2), 96–98.
Favrais, G., van de Looij, Y., Fleiss, B., Ramanantsoa, N., Bonnin, P., Stoltenburg-Didinger, G., et al.,
2011. Systemic inflammation disrupts the developmental program of white matter. Ann.
Neurol. 70 (4), 550–565.
Fellerhoff, B., Laumbacher, B., Mueller, N., Gu, S., Wank, R., 2007. Associations between
Chlamydophila infections, schizophrenia and risk of HLA-A10. Mol. Psychiatry 12 (3),
264–272.
Fillman, S.G., Cloonan, N., Miller, L.C., Weickert, C.S., 2013. Markers of inflammation in the pre-
frontal cortex of individuals with schizophrenia. Mol. Psychiatry 18 (2), 133.
Flatow, J., Buckley, P., Miller, B.J., 2013. Meta-analysis of oxidative stress in schizophrenia. Biol.
Psychiatry 74 (6), 400–409.
Fond, G., Hamdani, N., Kapczinski, F., Boukouaci, W., Drancourt, N., Dargel, A., et al., 2013. Effec-
tiveness and tolerance of anti-inflammatory drugs' add-on therapy in major mental disor-
ders: a systematic qualitative review. Acta Psychiatr. Scand. 129 (3), 163–179.
Fudenberg, H.H., Whitten, H.D., Merler, E., Farmati, O., 1983. Is schizophrenia an immunologic
receptor disorder? Med. Hypotheses 12 (1), 85–93.
Garver, D.L., Tamas, R.L., Holcomb, J.A., 2003. Elevated interleukin-6 in the cerebrospinal fluid of
a previously delineated schizophrenia subtype. Neuropsychopharmacology 28 (8),
1515–1520.
Gattaz, W.F., Abrahao, A.L., Foccacia, R., 2004. Childhood meningitis, brain maturation and the
risk of psychosis. Eur. Arch. Psychiatry Clin. Neurosci. 254 (1), 23–26.
Gogtay, N., Lu, A., Leow, A.D., Klunder, A.D., Lee, A.D., Chavez, A., et al., 2008. Three-dimensional
brain growth abnormalities in childhood-onset schizophrenia visualized by using tensor-
based morphometry. Proc. Natl. Acad. Sci. U. S. A. 105 (41), 15979–15984.
Hagberg, H., Gressens, P., Mallard, C., 2012. Inflammation during fetal and neonatal life: implica-
tions for neurologic and neuropsychiatric disease in children and adults. Ann. Neurol. 71
(4), 444–457.
Hashimoto, M., Maekawa, M., Katakura, M., Hamazaki, K., Matsuoka, Y., 2014. Possibility of poly-
unsaturated fatty acids for the prevention and treatment of neuropsychiatric illnesses.
J. Pharmacol. Sci. 124 (3), 294–300.
Hayes, L.N., Severance, E.G., Leek, J.T., Gressitt, K.L., Rohleder, C., Coughlin, J.M., et al., 2014. In-
flammatory molecular signature associated with infectious agents in psychosis. Schizophr.
Bull. 40 (5), 963–972.
Hercher, C., Chopra, V., Beasley, C.L., 2014. Evidence for morphological alterations in prefrontal
white matter glia in schizophrenia and bipolar disorder. J. Psychiatry Neurosci. 39 (6),
376–385.
Huerta, I., McCullumsmith, R.E., Haroutunian, V., Gimenez-Amaya, J.M., Meador-Woodruff, J.H.,
2006. Expression of excitatory amino acid transporter interacting protein transcripts in
the thalamus in schizophrenia. Synapse 59 (7), 394–402.
Hwang, Y., Kim, J., Shin, J.Y., Kim, J.I., Seo, J.S., Webster, M.J., et al., 2013. Gene expression
profiling by mRNA sequencing reveals increased expression of immune/
inflammation-related genes in the hippocampus of individuals with schizophrenia.
Transl Psychiatry 3, e321.
Insel, T.R., 2011. Rethinking schizophrenia. Nature 468 (7321), 187–193.
Jaaro-Peled, H., Ayhan, Y., Pletnikov, M.V., Sawa, A., 2009a. Review of pathological hallmarks of
schizophrenia: comparison of genetic models with patients and nongenetic models.
Schizophr. Bull. 36 (2), 301–313.
Jaaro-Peled, H., Hayashi-Takagi, A., Seshadri, S., Kamiya, A., Brandon, N.J., Sawa, A., 2009b.
Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal
brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci. 32 (9),
485–495.
Jia, P., Wang, L., Meltzer, H.Y., Zhao, Z., 2010. Common variants conferring risk of schizophrenia:
a pathway analysis of GWAS data. Schizophr. Res. 122 (1–3), 38–42.
Job, D.E., Whalley, H.C., Johnstone, E.C., Lawrie, S.M., 2005. Grey matter changes over time in
high risk subjects developing schizophrenia. Neuroimage 25 (4), 1023–1030.
Downloaded for Perpus FK UNPAD 02 (perpus.fkunpad02@gmail.com) at Padjadjaran University from ClinicalKey.com by Elsevier on May 26, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
21
Job, D.E., Whalley, H.C., McIntosh, A.M., Owens, D.G., Johnstone, E.C., Lawrie, S.M., 2006. Grey
matter changes can improve the prediction of schizophrenia in subjects at high risk. BMC
Med. 4, 29.
Kawasaki, H., Iwamuro, S., 2008. Potential roles of histones in host defense as antimicrobial
agents. Infect. Disord. Drug Targets 8 (3), 195–205.
Kenk, M., Selvanathan, T., Rao, N., Suridjan, I., Rusjan, P., Remington, G., et al., 2014. Imaging neu-
roinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-
FEPPA. Schizophr. Bull. 41 (1), 85–93.
Khandaker, G.M., Zammit, S., Lewis, G., Jones, P.B., 2013. A population-based study of atopic dis-
orders and inflammatory markers in childhood before psychotic experiences in adoles-
cence. Schizophr. Res. 152 (1), 139–145.
Khandaker, G.M., Pearson, R.M., Zammit, S., Lewis, G., Jones, P.B., 2014a. Association of serum in-
terleukin 6 and C-reactive protein in childhood with depression and psychosis in young
adult life: a population-based longitudinal study. JAMA Psychiatry 71 (10), 1121–1128.
Khandaker, G.M., Stochl, J., Zammit, S., Lewis, G., Jones, P.B., 2014b. Childhood Epstein–Barr Virus
infection and subsequent risk of psychotic experiences in adolescence: a population-based
prospective serological study. Schizophr. Res. 158 (1–3), 19–24.
Kim, S., Zavitsanou, K., Gurguis, G., Webster, M.J., 2012. Neuropathology markers and pathways
associated with molecular targets for antipsychotic drugs in postmortem brain tissues: ex-
ploration of drug targets through the Stanley Neuropathology Integrative Database. Eur.
Neuropsychopharmacol. 22 (10), 683–694.
Kohen, R., Nyska, A., 2002. Oxidation of biological systems: oxidative stress phenomena, antiox-
idants, redox reactions, and methods for their quantification. Toxicol. Pathol. 30 (6),
620–650.
Kreisl, W.C., Jenko, K.J., Hines, C.S., Lyoo, C.H., Corona, W., Morse, C.L., et al., 2012. A genetic poly-
morphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand bind-
ing in human brain to this putative biomarker of neuroinflammation. J. Cereb. Blood Flow
Metab. 33 (1), 53–58.
Kroken, R.A., Loberg, E.M., Dronen, T., Gruner, R., Hugdahl, K., Kompus, K., et al., 2014. A critical
review of pro-cognitive drug targets in psychosis: convergence on myelination and inflam-
mation. Front. Psychiatry 5, 11.
Kundakovic, M., Chen, Y., Costa, E., Grayson, D.R., 2007. DNA methyltransferase inhibitors coor-
dinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes.
Mol. Pharmacol. 71 (3), 644–653.
Kunz, M., Cereser, K.M., Goi, P.D., Fries, G.R., Teixeira, A.L., Fernandes, B.S., et al., 2011. Serum
levels of IL-6, IL-10 and TNF-alpha in patients with bipolar disorder and schizophrenia: dif-
ferences in pro- and anti-inflammatory balance. Rev. Bras. Psiquiatr. 33 (3), 268–274.
Laan, W., Grobbee, D.E., Selten, J.P., Heijnen, C.J., Kahn, R.S., Burger, H., 2010. Adjuvant aspirin
therapy reduces symptoms of schizophrenia spectrum disorders: results from a random-
ized, double-blind, placebo-controlled trial. J. Clin. Psychiatry 71 (5), 520–527.
Le Hellard, S., Muhleisen, T.W., Djurovic, S., Ferno, J., Ouriaghi, Z., Mattheisen, M., et al., 2008.
Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors
controlling cellular lipogenesis, are associated with schizophrenia in German and Scandina-
vian samples. Mol. Psychiatry 15 (5), 463–472.
Leviton, A., Gressens, P., 2007. Neuronal damage accompanies perinatal white-matter damage.
Trends Neurosci. 30 (9), 473–478.
Levkovitz, Y., Mendlovich, S., Riwkes, S., Braw, Y., Levkovitch-Verbin, H., Gal, G., et al., 2010. A
double-blind, randomized study of minocycline for the treatment of negative and cognitive
symptoms in early-phase schizophrenia. J. Clin. Psychiatry 71 (2), 138–149.
Leweke, F.M., Gerth, C.W., Koethe, D., Klosterkotter, J., Ruslanova, I., Krivogorsky, B., et al., 2004.
Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur. Arch.
Psychiatry Clin. Neurosci. 254 (1), 4–8.
Matthews, P.R., Harrison, P.J., 2011. A morphometric, immunohistochemical, and in situ hybrid-
ization study of the dorsal raphe nucleus in major depression, bipolar disorder, schizophre-
nia, and suicide. J. Affect. Disord. 137 (1–3), 125–134.
Mayilyan, K.R., Arnold, J.N., Presanis, J.S., Soghoyan, A.F., Sim, R.B., 2006. Increased complement
classical and mannan-binding lectin pathway activities in schizophrenia. Neurosci. Lett. 404
(3), 336–341.
Meda, S.A., Ruano, G., Windemuth, A., O'Neil, K., Berwise, C., Dunn, S.M., et al., 2014. Multivariate
analysis reveals genetic associations of the resting default mode network in psychotic bipo-
lar disorder and schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 111 (19), E2066–E2075.
Mehler, M.F., Kessler, J.A., 1998. Cytokines in brain development and function. Adv. Protein
Chem. 52, 223–251.
Meisenzahl, E.M., Rujescu, D., Kirner, A., Giegling, I., Kathmann, N., Leinsinger, G., et al., 2001. As-
sociation of an interleukin-1beta genetic polymorphism with altered brain structure in pa-
tients with schizophrenia. Am. J. Psychiatry 158 (8), 1316–1319.
Meyer, U., 2011. Anti-inflammatory signaling in schizophrenia. Brain Behav. Immun. 25 (8),
1507–1518.
Meyer, U., Weiner, I., McAlonan, G.M., Feldon, J., 2010. The neuropathological contribution of
prenatal inflammation to schizophrenia. Expert. Rev. Neurother. 11 (1), 29–32.
Miller, B.J., Buckley, P., Seabolt, W., Mellor, A., Kirkpatrick, B., 2011. Meta-analysis of cytokine al-
terations in schizophrenia: clinical status and antipsychotic effects. Biol. Psychiatry 70 (7),
663–671.
Monji, A., Kato, T., Kanba, S., 2009. Cytokines and schizophrenia: microglia hypothesis of schizo-
phrenia. Psychiatry Clin. Neurosci. 63 (3), 257–265.
Mousa, A., Seiger, A., Kjaeldgaard, A., Bakhiet, M., 1999. Human first trimester forebrain cells ex-
press genes for inflammatory and anti-inflammatory cytokines. Cytokine 11 (1), 55–60.
Muller, N., 2014. Immunology of schizophrenia. Neuroimmunomodulation 21 (2–3), 109–116.
Muller, N., Schwarz, M.J., 2010. Immune system and schizophrenia. Curr. Immunol. Rev. 6 (3),
213–220.
Muller, N., Ulmschneider, M., Scheppach, C., Schwarz, M.J., Ackenheil, M., Moller, H.J., et al., 2004.
COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations
and clinical effects of celecoxib add-on therapy. Eur. Arch. Psychiatry Clin. Neurosci. 254
(1), 14–22.
Muller, N., Krause, D., Dehning, S., Musil, R., Schennach-Wolff, R., Obermeier, M., et al., 2010.
Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-
blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment.
Schizophr. Res. 121 (1–3), 118–124.
Nathan, C., Shiloh, M.U., 2000. Reactive oxygen and nitrogen intermediates in the relationship
between mammalian hosts and microbial pathogens. Proc. Natl. Acad. Sci. U. S. A. 97
(16), 8841–8848.
22 C.C. Watkins, S.R. Andrews / Schizophrenia Research 176 (2016) 14–22
Noto, C., Ota, V.K., Gouveia, E.S., Rizzo, L.B., Spindola, L.M., Honda, P.H., et al., 2014. Effects
of risperidone on cytokine profile in drug naive first episode psychosis. Int.
J. Neuropsychopharmacol. 18 (4), 1–8.
Pathmanandavel, K., Starling, J., Dale, R.C., Brilot, F., 2013. Autoantibodies and the immune hy-
pothesis in psychotic brain diseases: challenges and perspectives. Clin. Dev. Immunol.
2013, 257184.
Patterson, P.H., 2009. Immune involvement in schizophrenia and autism: etiology, pathology
and animal models. Behav. Brain Res. 204 (2), 313–321.
Pesce, M., Ferrone, A., Rizzuto, A., Tatangelo, R., Iezzi, I., Ladu, S., et al., 2014. The SHP-1 expres-
sion is associated with cytokines and psychopathological status in unmedicated first epi-
sode schizophrenia patients. Brain Behav. Immun. 41, 251–260.
Poels, E.M., Kegeles, L.S., Kantrowitz, J.T., Slifstein, M., Javitt, D.C., Lieberman, J.A., et al., 2013. Im-
aging glutamate in schizophrenia: review of findings and implications for drug discovery.
Mol. Psychiatry 19 (1), 20–29.
Potvin, S., Stip, E., Sepehry, A.A., Gendron, A., Bah, R., Kouassi, E., 2008. Inflammatory cytokine
alterations in schizophrenia: a systematic quantitative review. Biol. Psychiatry 63 (8),
801–808.
Prasad, K.M., Upton, C.H., Nimgaonkar, V.L., Keshavan, M.S., 2014. Differential susceptibility of
white matter tracts to inflammatory mediators in schizophrenia: an integrated DTI study.
Schizophr. Res. 161 (1), 119–125.
Purcell, S.M., Wray, N.R., Stone, J.L., Visscher, P.M., O'Donovan, M.C., Sullivan, P.F., et al., 2009.
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Na-
ture 460 (7256), 748–752.
Radewicz, K., Garey, L.J., Gentleman, S.M., Reynolds, R., 2000. Increase in HLA-DR immunoreac-
tive microglia in frontal and temporal cortex of chronic schizophrenics. J. Neuropathol. Exp.
Neurol. 59 (2), 137–150.
Radomska, K.J., Halvardson, J., Reinius, B., Lindholm Carlstrom, E., Emilsson, L., Feuk, L., et al.,
2013. RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in
human astrocytes. Hum. Mol. Genet. 22 (7), 1373–1382.
Rapoport, J.L., Giedd, J.N., Gogtay, N., 2012. Neurodevelopmental model of schizophrenia: update
2012. Mol. Psychiatry 17 (12), 1228–1238.
Ripke, S., O'Dushlaine, C., Chambert, K., Moran, J.L., Kahler, A.K., Akterin, S., et al., 2013. Genome-
wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45 (10),
1150–1159.
Rossler, W., Salize, H.J., van Os, J., Riecher-Rossler, A., 2005. Size of burden of schizophrenia and
psychotic disorders. Eur. Neuropsychopharmacol. 15 (4), 399–409.
Rothermundt, M., Ohrmann, P., Abel, S., Siegmund, A., Pedersen, A., Ponath, G., et al., 2007. Glial
cell activation in a subgroup of patients with schizophrenia indicated by increased S100B
serum concentrations and elevated myo-inositol. Prog. Neuropsychopharmacol. Biol. Psy-
chiatry 31 (2), 361–364.
Rowland, L.M., Kontson, K., West, J., Edden, R.A., Zhu, H., Wijtenburg, S.A., et al., 2012. In vivo
measurements of glutamate, GABA, and NAAG in schizophrenia. Schizophr. Bull. 39 (5),
1096–1104.
Sathyasaikumar, K.V., Stachowski, E.K., Wonodi, I., Roberts, R.C., Rassoulpour, A., McMahon, R.P.,
et al., 2010. Impaired kynurenine pathway metabolism in the prefrontal cortex of individ-
uals with schizophrenia. Schizophr. Bull. 37 (6), 1147–1156.
Schwarcz, R., Rassoulpour, A., Wu, H.Q., Medoff, D., Tamminga, C.A., Roberts, R.C., 2001. In-
creased cortical kynurenate content in schizophrenia. Biol. Psychiatry 50 (7), 521–530.
Schwieler, L., Larsson, M.K., Skogh, E., Kegel, M.E., Orhan, F., Abdelmoaty, S., et al., 2014. Increased
levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance
for activation of the kynurenine pathway. J. Psychiatry Neurosci. 39 (6), 140126.
Selten, J.P., Frissen, A., Lensvelt-Mulders, G., Morgan, V.A., 2009. Schizophrenia and 1957 pan-
demic of influenza: meta-analysis. Schizophr. Bull. 36 (2), 219–228.
Severance, E.G., Yolken, R.H., Eaton, W.W., 2014a. Autoimmune diseases, gastrointestinal disor-
ders and the microbiome in schizophrenia: more than a gut feeling. Schizophr. Res. (pii:
S0920-9964(14)00319-3. doi: [Epub ahead of print]).
Severance, E.G., Gressitt, K.L., Buka, S.L., Cannon, T.D., Yolken, R.H., 2014b. Maternal complement
C1q and increased odds for psychosis in adult offspring. Schizophr. Res. 159 (1), 14–19.
Shi, L., Tu, N., Patterson, P.H., 2005. Maternal influenza infection is likely to alter fetal brain de-
velopment indirectly: the virus is not detected in the fetus. Int. J. Dev. Neurosci. 23 (2–3),
299–305.
Smesny, S., Kunstmann, C., Kunstmann, S., Willhardt, I., Lasch, J., Yotter, R.A., et al., 2010. Phos-
pholipase A(2) activity in first episode schizophrenia: associations with symptom severity
and outcome at week 12. World J. Biol. Psychiatry 12 (8), 598–607.
Downloaded for Perpus FK UNPAD 02 (perpus.fkunpad02@gmail.com) at Padjadjaran University from ClinicalKey.com by Elsevier on May 26, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Sommer, I.E., van Westrhenen, R., Begemann, M.J., de Witte, L.D., Leucht, S., Kahn, R.S., 2013. Ef-
ficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia:
an update. Schizophr. Bull. 40 (1), 181–191.
Sorensen, H.J., Mortensen, E.L., Parnas, J., Mednick, S.A., 2006. Premorbid neurocognitive func-
tioning in schizophrenia spectrum disorder. Schizophr. Bull. 32 (3), 578–583.
Sorensen, H.J., Mortensen, E.L., Reinisch, J.M., Mednick, S.A., 2009. Association between prenatal
exposure to bacterial infection and risk of schizophrenia. Schizophr. Bull. 35 (3), 631–637.
Spangaro, M., Bosia, M., Zanoletti, A., Bechi, M., Cocchi, F., Pirovano, A., et al., 2012. Cognitive dys-
function and glutamate reuptake: effect of EAAT2 polymorphism in schizophrenia.
Neurosci. Lett. 522 (2), 151–155.
Stan, A.D., Ghose, S., Zhao, C., Hulsey, K., Mihalakos, P., Yanagi, M., et al., 2014. Magnetic reso-
nance spectroscopy and tissue protein concentrations together suggest lower glutamate
signaling in dentate gyrus in schizophrenia. Mol. Psychiatry 20 (4), 433–439.
Steen, R.G., Mull, C., McClure, R., Hamer, R.M., Lieberman, J.A., 2006. Brain volume in first-
episode schizophrenia: systematic review and meta-analysis of magnetic resonance imag-
ing studies. Br. J. Psychiatry 188, 510–518.
Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., et al., 2009.
Common variants conferring risk of schizophrenia. Nature 460 (7256), 744–747.
Steiner, J., Bernstein, H.G., Bielau, H., Farkas, N., Winter, J., Dobrowolny, H., et al., 2008a. S100B-
immunopositive glia is elevated in paranoid as compared to residual schizophrenia: a mor-
phometric study [Research Support, Non-U.S. Gov't] J. Psychiatr. Res. 42 (10), 868–876.
Steiner, J., Bielau, H., Brisch, R., Danos, P., Ullrich, O., Mawrin, C., et al., 2008b. Immunological as-
pects in the neurobiology of suicide: elevated microglial density in schizophrenia and de-
pression is associated with suicide. J. Psychiatr. Res. 42 (2), 151–157.
Steiner, J., Bogerts, B., Sarnyai, Z., Walter, M., Gos, T., Bernstein, H.G., et al., 2011a. Bridging the
gap between the immune and glutamate hypotheses of schizophrenia and major depres-
sion: potential role of glial NMDA receptor modulators and impaired blood–brain barrier
integrity. World J. Biol. Psychiatry 13 (7), 482–492.
Steiner, J., Walter, M., Gos, T., Guillemin, G.J., Bernstein, H.G., Sarnyai, Z., et al., 2011b. Severe de-
pression is associated with increased microglial quinolinic acid in subregions of the anterior
cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission?
J. Neuroinflammation 8, 94.
Stevens, J.R., 1983. Pathophysiology of schizophrenia. Clin. Neuropharmacol. 6 (2), 77–90.
Suvisaari, J.M., Haukka, J.K., Tanskanen, A.J., Lonnqvist, J.K., 1999. Decline in the incidence of
schizophrenia in Finnish cohorts born from 1954 to 1965. Arch. Gen. Psychiatry 56 (8),
733–740.
Swerdlow, N.R., van Bergeijk, D.P., Bergsma, F., Weber, E., Talledo, J., 2009. The effects of
memantine on prepulse inhibition. Neuropsychopharmacology 34 (7), 1854–1864.
Takano, A., Arakawa, R., Ito, H., Tateno, A., Takahashi, H., Matsumoto, R., et al., 2010. Peripheral
benzodiazepine receptors in patients with chronic schizophrenia: a PET study with
[11C]DAA1106. Int. J. Neuropsychopharmacol. 13 (7), 943–950.
Tang, B., Capitao, C., Dean, B., Thomas, E.A., 2012. Differential age- and disease-related effects on
the expression of genes related to the arachidonic acid signaling pathway in schizophrenia.
Psychiatry Res. 196 (2–3), 201–206.
Tomasik, J., Rahmoune, H., Guest, P.C., Bahn, S., 2014. Neuroimmune biomarkers in schizophre-
nia. Schizophr. Res. (pii: S0920-9964(14)00382-x. doi: [Epub ahead of print]).
Torrey, E.F., Miller, J., Rawlings, R., Yolken, R.H., 1997. Seasonality of births in schizophrenia and
bipolar disorder: a review of the literature. Schizophr. Res. 28 (1), 1–38.
Upthegrove, R., Manzanares-Teson, N., Barnes, N.M., 2014. Cytokine function in medication-
naive first episode psychosis: a systematic review and meta-analysis. Schizophr. Res. 155
(1–3), 101–108.
van Os, J., Kapur, S., 2009. Schizophrenia. Lancet 374 (9690), 635–645.
Watkins, C.C., Sawa, A., Pomper, M.G., 2014. Glia and immune cell signaling in bipolar disorder:
insights from neuropharmacology and molecular imaging to clinical application. Transl Psy-
chiatry 4, e350.
Wierzba-Bobrowicz, T., Lewandowska, E., Lechowicz, W., Stepien, T., Pasennik, E., 2005. Quanti-
tative analysis of activated microglia, ramified and damage of processes in the frontal and
temporal lobes of chronic schizophrenics. Folia Neuropathol. 43 (2), 81–89.
Yudofsky, S.C., 2009. Contracting schizophrenia: lessons from the influenza epidemic of
1918–1919. JAMA 301 (3), 324–326.
Zheng, L.T., Hwang, J., Ock, J., Lee, M.G., Lee, W.H., Suk, K., 2008. The antipsychotic spiperone at-
tenuates inflammatory response in cultured microglia via the reduction of proinflammato-
ry cytokine expression and nitric oxide production. J. Neurochem. 107 (5), 1225–1235.