Download Inflammatory processes in schizophrenia: A

Pharmacology & Therapeutics 132 (2011) 96–110
Contents lists available at ScienceDirect
Pharmacology & Therapeutics
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h a r m t h e r a
Inflammatory processes in schizophrenia: A promising neuroimmunological target
for the treatment of negative/cognitive symptoms and beyond
Urs Meyer a,⁎, Markus J. Schwarz b, Norbert Müller b
a
b
Physiology and Behaviour Laboratory, Swiss Federal Institute of Technology (ETH) Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Nussbaumstrasse 7, 80336 München, Germany
a r t i c l e
i n f o
a b s t r a c t
Emerging evidence indicates that schizophrenia is associated with activated peripheral and central
inflammatory responses. Such inflammatory processes seem to be influenced by a number of environmental
and genetic predisposition factors, and they may critically depend on and contribute to the progressive nature
of schizophrenic disease. There is also appreciable evidence to suggest that activated inflammatory responses
can undermine disease-relevant affective, emotional, social, and cognitive functions, so that inflammatory
processes may be particularly relevant for the precipitation of negative and cognitive symptoms of
schizophrenia. Recent clinical trials of anti-inflammatory pharmacotherapy in this disorder provide promising
results by showing superior beneficial treatment effects when standard antipsychotic drugs are coadministered with anti-inflammatory compounds, as compared with treatment outcomes using antipsychotic
drugs alone. Given the limited efficacy of currently available antipsychotic drugs to ameliorate negative and
cognitive symptoms, the further exploration of inflammatory mechanisms and anti-inflammatory strategies
may open fruitful new avenues for improved treatment of symptoms undermining affective, emotional, social
and cognitive functions pertinent to schizophrenic disease.
© 2011 Elsevier Inc. All rights reserved.
Keywords:
Antipsychotic drugs
Astrocytes
Cyclooxygenase
Cytokines
Inflammation
Microglia
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.
Main components of the inflammatory response system . . . . . . . . . . . . . . . . . . . . . . .
3.
Inflammatory signs in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.
Sources of activated inflammatory responses in schizophrenia . . . . . . . . . . . . . . . . . . . .
5.
Relevance of inflammatory processes to distinct symptom classes of schizophrenia . . . . . . . . . .
6.
Immunomodulatory effects of antipsychotic drugs and anti-inflammatory treatment strategies in schizophrenia
7.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
96
97
98
98
100
98
101
100
103
100
106
100
106
101
106
1. Introduction
Abbreviations: 3-OHKY, 3-hydroxykynurenine; APD, antipsychotic drug; CNS, central
nervous system; COX, cyclooxygenase; CRP, C-reactive protein; CSF, cerebrospinal fluid; DA,
dopamine; GABA, γ-aminobutyric acid; GWAS, genome-wide association studies; HPA axis,
hypothalamic–pituitary–adrenal axis; IDO, indoleamine 2,3-dioxygenase; IL, interleukin;
KYNA, kynurenic acid; LPS, lipopolysaccharide; MHC, major histocompatibility complex; NA,
noradrenalin; nAChR, nicotinic acetylcholine receptor; NMDA, N-methyl-D-aspartate; PGE2,
prostaglandin E2; QUIN, quinolinic acid; TGF, transforming growth factor; TH, tyrosine
hydroxylase; TH cells, T helper cells; TNF, tumor necrosis factor.
⁎ Corresponding author. Tel.: +41 44 655 7403; fax: +41 44 655 7203.
E-mail address: [email protected] (U. Meyer).
0163-7258/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.pharmthera.2011.06.003
Schizophrenia is a chronic form of psychotic illness that affects
approximately 1% of the population worldwide (Tandon et al., 2008; van
Os & Kapur, 2009). The onset of full-blown schizophrenic disease is
typically in late adolescence or early adulthood. The disorder includes
distinct but often co-existing symptom classes which are commonly
referred to as positive, negative and cognitive symptoms (Tandon et al.,
2009). Positive symptoms are features that are normally not present in
healthy individuals but appear as a result of the disease. These include
visual and/or auditory hallucinations, delusions, paranoia, and major
thought disorders. Negative symptoms refer to features that are
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
normally present, but are reduced or absent as a result of the disease
process, including social withdrawal, apathy, anhedonia, alogia, and
behavioral perseveration. Cognitive symptoms of schizophrenia typically involve disturbances in executive functions, working memory
impairment, and inability to sustain attention. Taken together,
schizophrenia is characterized by a wide spectrum of behavioral and
cognitive dysfunctions that can readily undermine basic human
processes of perception and judgment.
There is increasing recognition of the importance of negative and
cognitive symptoms in schizophrenia, partly because currently available
antipsychotic drugs (APDs) show a limited clinical efficacy in improving
these dysfunctions (Bowie & Harvey, 2006; Insel, 2010; Tandon et al.,
2010). Negative symptoms are typically classified as primary or
secondary, with primary negative symptoms representing a core feature
intrinsic to the disorder, whilst secondary negative symptoms are
temporary and often attributable to effects imposed by acute psychotic
episodes and/or APD treatment (Möller, 2007). Similar to the primary
negative symptoms, cognitive symptoms of schizophrenia appear to be
a core feature of the disorder and represent a major contributor to
functional disability (Elvevåg & Goldberg, 2000; Bowie & Harvey, 2006).
Both primary negative as well as cognitive symptoms often precede the
onset of full-blown psychotic episodes and persist subsequent to the
pharmacologically controlled resolution of acute psychotic phases
(Reichenberg, 2005; Möller, 2007).
The pathophysiology of schizophrenia likely involves neurochemical
imbalances in various neurotransmitter systems. Alterations in the
central dopamine (DA) system have been discussed for decades,
originally based on evidence that the therapeutically effective APDs
act, at least in part, by blocking DA receptors, especially the DA D2
receptor subclass; and that DA-stimulating drugs can induce psychosislike behavior in non-psychotic human subjects and exacerbate
(positive) symptoms in schizophrenic patients (Carlsson et al., 2001;
Howes & Kapur, 2009). Subsequently, the putative impact of a
hypofunctioning cortical DA system has been incorporated into the
theories of altered DA functions in schizophrenia (Carlsson et al., 2001;
Howes & Kapur, 2009). In addition to these cortical–subcortical DA
imbalances, functional changes in serotonergic and glutamatergic
transmission seem highly relevant for the disorder (Abi-Dargham et
al., 1997; Carlsson et al., 2001; Coyle et al., 2003; Javitt, 2007). The
current consensus is that alterations of these neurotransmitter systems
either lead to a functional imbalance of DA transmission via interaction
with the DA system, and/or contribute pathophysiologically to
schizophrenia by direct non-dopaminergic actions. Finally, alterations
in the central γ-aminobutyric acid (GABA) (Benes & Berretta, 2001;
Lewis et al., 2005) and cholinergic (Martin & Freedman, 2007) systems
have also been in the focus of attention by virtue of their modulatory
functions at the relevant synapses and their impact on cognitive
functions known to be impaired in schizophrenia.
Besides these neurochemical and neuropathological changes,
schizophrenia has also been linked to numerous alterations in basic
physiological and metabolic functions, including cardiovascular disease,
type-2 diabetes, and obesity (Marder et al., 2004). A large body of
evidence further implicates a spectrum of immunological abnormalities
in this disorder. Indeed, the idea that altered immune functions may
play an important role in schizophrenia has a long history (DeLisi &
Wyatt, 1982; Müller et al., 1991; Smith, 1991; Müller et al., 2000).
However, it is not unusual that attempts to explain some of the
underlying pathophysiological mechanisms by immune abnormalities
are met with skepticism (DeLisi, 1996). One has often raised the issue as
to whether the presence of immunological alterations may provide a
genuine contribution to schizophrenia pathogenesis, or whether such
immune alterations should be considered a pathophysiologically
irrelevant epiphenomenon. There is now appreciable evidence to
assume that the former may indeed be the case, and several lines of
recent research have readily boosted renewed awareness of the
immunological facets of schizophrenia (Müller & Schwarz, 2010).
97
One emerging aspect of immune changes in schizophrenia relates to
activated inflammatory processes (Fan et al., 2007a; Potvin et al., 2008;
Drexhage et al., 2010). In this article, we discuss that activated
inflammatory responses in schizophrenia may provide a promising
neuroimmunological target for the treatment of multiple psychopathological symptoms, including those pertinent to the negative and
cognitive symptoms of schizophrenia. First, the basic principles and
components of inflammation are outlined, followed by an up-to-date
summary of inflammatory signs in schizophrenia and their potential
origins. We then discuss behavioral and neuronal effects of inflammation, with a special emphasis on those effects that seem closely linked to
the negative and cognitive symptoms of schizophrenia. Finally, we
highlight the immunomodulatory effects of conventional APDs and
discuss recent progress in treating schizophrenic disease by adjunctive
anti-inflammatory pharmacotherapy.
2. Main components of the inflammatory response system
Inflammation is one of the first defense mechanisms of the innate
immune system to infection and other physiological insults such as
tissue damage or stress (Gallin et al., 1999). Typically, it is characterized
by redness and swelling of infected/wounded tissue and is promoted by
a number of secreted pro-inflammatory factors, including prostaglandins, leukotrienes, pro-inflammatory cytokines and chemokines. Prostaglandins are import mediators of the febrile response and of blood
vessel dilation, whereas leukotrienes together with chemokines are
critical for attracting leukocytes to sites of infection and/or tissue
damage (Gallin et al., 1999). Cytokines have wide-ranging roles in the
innate and adaptive immune systems, where they help regulate the
recruitment and activation of lymphocytes as well as immune cell
differentiation and homeostasis (Curfs et al., 1997). In addition, some
cytokines possess direct effector mechanisms, including induction of
cell apoptosis and inhibition of protein synthesis (Curfs et al., 1997).
Members of the pro-inflammatory cytokine family, including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, are essential to the
inflammatory response by contributing to febrile reactions, activating
phagocytotic cells such as macrophages or dendritic cells, facilitating
vascular permeability, and promoting the release of plasma-derived
inflammatory mediators such as bradykinin and components of the
complement system. In the periphery, pro-inflammatory cytokines are
produced and released to a great extent by activated endothelial cells
and cells of the mononuclear phagocyte system (monocytes, macrophages and monocyte-derived dendritic cells). The synthesis of proinflammatory molecules is strongly stimulated upon activation of the
innate immune system. This most often occurs upon binding of
microbe-specific components by a special class of receptors known as
pathogen recognition receptors, or when damaged or infected cells send
out alarm signals, many of which are recognized by the same receptors
as those that recognize pathogens (Janeway & Medzhitov, 2002;
Mogensen, 2009).
Under normal conditions, inflammation is controlled by various
homeostatic processes that limit or counteract inflammation once it has
been induced by a pro-inflammatory stimulus such as infection (Serhan
& Savill, 2005). Such control mechanisms ensure that inflammatory
processes efficiently remove invading pathogens and contribute to
tissue repair and wound healing without inducing collateral damage to
non-infected, healthy and unwounded tissue. Dysfunction of such
surveillance mechanisms may lead to persistent inflammation, known
from numerous pathological conditions such as rheumatoid arthritis,
atherosclerosis, inflammatory bowel disease, and Crohn's disease
(Serhan & Savill, 2005; Briand & Muller, 2010).
In the central nervous system (CNS), microglia and astrocytes are the
major immunocompetent cells regulating both the induction as well as
limitation of inflammatory processes (Seth & Koul, 2008; Ransohoff &
Perry, 2009). This is achieved through the synthesis of cytokines, up- or
down-regulation of various cell surface receptors such as pathogen
98
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
recognition receptors, cytokine receptors, and numerous receptors
crucial for antigen presentation. Acting as the first and main form of
active immune defense in the brain, microglia are considered to be the
resident macrophages of the CNS, which constantly scavenge the CNS
for damaged neurons, plaques, and infectious agents (Ransohoff & Perry,
2009). Microglia appear to play crucial roles in both neuronal protection
and pathology, and are often referred to as a “double-edged sword”
(Block et al., 2007). On the one hand, they secrete neurotrophic factors
pivotal for cellular repair, and recruit immune cells into the brain for
clearance of infection or cellular debris. On the other hand, chronic or
exaggerated microglial activation is linked to excessive secretion of proinflammatory factors and has been linked to (progressive) neurodegenerative processes (Block et al., 2007). With regards to astroctyes, it
has been considered for long that the main roles of these glial cells are
related to neuronal support functions. However, accumulating evidence
suggests that astrocytes exert a much wider spectrum of functions,
including regulation of neuronal differentiation, axonal guidance,
synapse formation, and brain plasticity (Seth & Koul, 2008). Of note,
astrocytes have also become the focus of attention due to their
modulatory effects on microglia cells: They seem to have noticeable
inhibitory as well as stimulatory influences on microglia functions
depending on the precise immune milieu in which astroctye–microglia
interactions take place (Wang, 2010; Bianchi et al., 2011; Zhang et al.,
2011).
3. Inflammatory signs in schizophrenia
3.1. Peripheral inflammation
Signs of peripheral inflammatory responses in schizophrenia have
typically been evidenced by the presence of elevated serum/plasma
levels or in-vitro production of specific pro-inflammatory factors,
including prostaglandin E2 (PGE2), C-reactive protein (CRP), and
numerous pro-inflammatory cytokines such as interleukin (IL)-1β, IL6, IL-8, and tumor necrosis factor (TNF)-α (for recent reviews, see Fan et
al., 2007a; Potvin et al., 2008; Drexhage et al., 2010). Table 1 provides a
summary of inflammatory markers that have been repeatedly described
to be altered in schizophrenic patients. Peripheral inflammatory
responses in schizophrenia further seem to involve aberrations in
circulating monocytes (Drexhage et al., 2010), which notably are one of
the main sources of pro-inflammatory molecule production and
secretion (Curfs et al., 1997; Gallin et al., 1999). Indeed, several studies
have reported significant increases in the absolute and/or relative
counts of monocytes and total white blood cells in schizophrenic
patients (Zorrilla et al., 1996; Rothermundt et al., 1998; Fan et al., 2010).
In addition, activated T helper 1 (TH1) lymphoyctes are also capable of
secreting appreciable amounts of pro-inflammatory cytokines (Curfs et
al., 1997; Gallin et al., 1999), and functional changes in TH1-mediated
pro-inflammatory activity have been found in schizophrenic patients
(Drexhage et al., 2011).
Emerging evidence suggests that in schizophrenia, increased proinflammatory activity concurs with enhanced anti-inflammatory peripheral responses. Among the most consistent findings in this context
are elevated peripheral levels and/or in-vitro production of soluble IL-1
receptor antagonist (sIL-1RA) and soluble IL-2 receptor (sIL-2R) (Maes et
al., 1994, 1996; Akiyama, 1999; Bresee & Rapaport, 2009). sIL-1RA binds
to IL-1 receptors in competition with IL-1α/β, but in contrast to the latter,
it fails to activate intracellular signaling cascades (Gabay et al., 2010).
Likewise, sIL-2R is shed from the cellular surface of activated immune
cells and efficiently blocks the biological activity of IL-2 by preventing its
binding to the membrane-anchored and signal-transducing IL-2 receptor
complex (Nelson & Willerford, 1998). sIL-1RA and sIL-2R can thus both
efficiently block pro-inflammatory effects typically associated with IL-1
and IL-2 signaling, respectively. Changes in the anti-inflammatory
response systems of schizophrenic patients may further involve
peripheral elevations in soluble TNF receptor (sTNFR), IL-10, and
transforming growth factor (TGF)-β (Maes et al., 2002; Kim et al.,
2004; Coelho et al., 2008; Hope et al., 2009; Kunz et al., 2011), all of which
are known to exert potent anti-inflammatory and/or immunosuppressive functions (Murray, 2006; Bradley, 2008; Yoshimura et al., 2010).
However, conflicting reports exist with regards to these markers in
schizophrenia (e.g., Naudin et al., 1997; Haack et al., 1999), so that the
nature and/or direction of their changes in schizophrenic patients still
awaits further validation.
In support of the notion that schizophrenia is associated with both
enhanced pro-inflammatory and anti-inflammatory activity, several
studies assessing within-subjects cytokine changes report concomitant
up-regulation of pro- and anti-inflammatory cytokines in affected
individuals (e.g., Maes et al., 2002; Kim et al., 2004). A recent study by
Drexhage et al. (2011) further indicates that this concurrent enhancement of pro- and anti-inflammatory activity can be readily extended to
the level of peripheral immune cells. More specially, it has been noted
that schizophrenic patients not only show higher percentages of proinflammatory monocytes, activated CD3+CD25+ T cells and proinflammatory TH17 cells, but they also display higher amounts of antiinflammatory CD4+CD25highFoxP3+ regulatory T cells and IL-4+
lymphocytes (Drexhage et al., 2011).
The concomitant up-regulation of pro- and and-inflammatory
markers in schizophrenia may not be unprecedented in view of the
inherent linkage and cross-regulation of the pro- and anti-inflammatory arms of the immune system (Gallin et al., 1999; Serhan & Savill,
2005). The relative potency of schizophrenic patients to mount
enhanced anti-inflammatory actions in response to the presence of
pro-inflammatory stimuli may readily be favorable in as much as this
would provide an efficient way to counteract and restrict on-going proinflammatory processes, thereby preventing the development of
progressive and potentially detrimental effects of chronic inflammation. Indeed, it is important to recognize that despite the signs of
enhanced pro-inflammatory responses, the severity of such responses
in schizophrenia seems relatively modest compared to pathologies that
are characterized by marked chronic inflammation such as rheumatoid
arthritis or atherosclerosis (Serhan & Savill, 2005). The inflammatory
response in schizophrenia is therefore often referred to as “low-grade
inflammation” (Fan et al., 2007a; Drexhage et al., 2010; Meyer et al.,
2011).
It needs to be pointed out that reports of peripheral cytokine
alterations in schizophrenia have not always been consistent between
individual studies. Several confounding factors have often been
discussed to contribute to discrepant outcomes, including smoking,
weight gain, and age (Hinze-Selch & Pollmächer, 2001; Maes et al.,
2002). In addition, it has been widely recognized that APDs can
markedly influence cytokine levels, especially with regards to their
serum/plasma concentrations (Drzyzga et al., 2006). Even though
differences in the precise medication status may readily complicate the
interpretation of individual findings, the immunomodulatory effects of
APDs appear to have considerable beneficial effects in the treatment of
schizophrenic disease. This issue is discussed in detail below (see
Section 6.1). It is also important to point out that inflammatory cytokine
abnormalities, including up-regulation of peripheral IL-1β, sIL-1RA, sIL2R, IL-6, IL-8, and TNF-α levels, have been described in medicationnaïve or minimally medicated first-episode schizophrenic patients (e.g.,
Akiyama, 1999; van Kammen et al., 1999; Theodoropoulou et al., 2001;
Zhang et al., 2002; Sirota et al., 2005; Na & Kim, 2007; Kim et al., 2009;
Song et al., 2009). It is therefore unlikely that inflammatory cytokine
changes in peripheral tissues and organs of schizophrenic patients may
stem solely from medication effects, but rather, they seem to represent a
genuine immunological phenotype of this disorder.
3.2. Central inflammation
Owing to their multiple roles in mediating and modulating
inflammatory processes in the CNS (Block et al., 2007; Ransohoff &
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
99
Table 1
Secreted immunological factors implicated in the inflammatory response in schizophrenia. The table summarizes the major cellular sources and biological activities of pro- and antiinflammatory molecules, and the various effects described in peripheral (serum/plasma) and central (CNS) systems of patients with schizophrenia. Symbols (↑) and (↓) denote
significant increases and decreases, respectively; symbol (↔) signifies no significant changes.
Factor
Main cellular source
Main biological activities
Effect in schizophrenia
References
IL-1β
Activated monocytes/macrophages;
endothelia cells; microglia.
Promotion of fever (endogenous pyrogen);
stimulation of other pro-inflammatory cytokines
and hematopoietic growth factors; induction of
acute-phase proteins; stimulation of HPA axis;
activation of T-, B- and endothelial cells.
Inhibition of IL-1 activity; homeostatic control
of inflammation through anti-inflammatory actions.
↑ (Serum/plasma)
Theodoropoulou et al., 2001;
Song et al., 2009.
Barak et al., 1995; Söderlund et al., 2009.
sIL-1RA
IL-2
Activated monocytes/macrophages;
endothelia cells; fibroblasts,
astroctyes.
TH1 cells
sIL-2RA
Activated T cells.
IL-6
Activated monocytes/macrophages;
T cells (TH2 and TH17 cells);
hepatocytes; osteoclasts; fibroblasts;
astrocytes.
Activation, growth, and differentiation of T cells;
promotion of antigen-specific immune responses;
stimulation of pro-inflammatory cytokine production
by polymorphonuclear neutrophils and natural
killer cells.
Inhibition of IL-2 activity; homeostatic control of
T cell activation.
Promotion of fever (endogenous pyrogen);
induction of acute-phase proteins; stimulation
of immunoglobulin-G production; activation of
T cells; stimulation of HPA axis.
↑/↓ (CNS)
↑ (Serum/plasma)
↓ (Serum/plasma)
↑ (CNS)
↑ (Serum/plasma)
Maes et al., 1996; Akiyama, 1999;
Sirota et al., 2005.
Toyooka et al., 2003
Barak et al., 1995; McAllister et al., 1995;
Kim et al., 2000; Zhang et al., 2002.
Licinio et al., 1993; Barak et al., 1995;
McAllister et al., 1995;
Rapaport et al., 1997.
Maes et al., 1994; Bresee and
Rapaport, 2009; Akiyama, 1999.
Barak et al., 1995.
Maes et al., 1994; Akiyama, 1999;
van Kammen et al., 1999;
Zhang et al., 2002; Na and
Kim, 2007; Kim et al., 2009.
van Kammen et al., 1999;
Garver et al., 2003.
Maes et al., 1994; Müller et al., 1997a.
Müller et al., 1997a.
Maes et al., 2002; Zhang et al., 2002.
↑ (Serum/plasma)
Maes et al., 2002; Kunz et al., 2011.
↑ (Serum/plasma)
Theodoropoulou et al., 2001;
Na and Kim, 2007; Kim et al., 2009;
Song et al., 2009.
↑ (Serum/plasma)
Coelho et al., 2008; Hope et al., 2009.
↑ (Serum/plasma)
Kim et al., 2004.
↑ (Serum/plasma)
Kaiya et al., 1989.
↑ (Serum/plasma)
Dickerson et al., 2007;
Fan et al., 2007b.
↓ (CSF)
↑/↔ (CNS)
↑/↔ (CNS)
↑ (Serum/plasma)
↓ (CSF)
↑ (Serum/plasma)
↑/↔ (CNS)
sIL-6R
IL-8
IL-10
Activated monocytes/macrophages;
hepatocytes; osteoclasts.
Activated monocytes/macrophages;
endothelia cells; fibroblasts.
Activated monocytes/macrophages;
T cells (TH2 cells); B cells.
TNF-α
Activated monocytes/macrophages;
T cells (TH1 cells); natural killer cells;
endothelia cells; microglia.
sTNFR
Virtually all nucleated cells.
TGF-β
Megakaryocytes; T cells (TH3 cells).
PGE2
All nucleated cells expressing
arachidonic acid.
Hepatocytes in response to proinflammatory signals (especially IL-6).
CRP
Augmentation of IL-6 responses by acting as
an IL-6 agonist.
Activation of neutrophils; chemotactic for
neutrophils, T cells and basophils.
Inhibition of pro-inflammatory cytokine
synthesis; inhibition of sepsis; promotion
of humoral immune responses involving
antibody secretion.
Promotion of fever (endogenous pyrogen) and
sepsis; direct cytotoxic effects by inducing
apoptosis; activation of monocytes, lymphocytes,
and endothelial cells.
Inhibition of TNF activity; homeostatic control
of inflammation through anti-inflammatory
actions.
Inhibition of pro-inflammatory cytokine
synthesis; inhibition of natural killer cell
activity and growth of T- and B-cells; in the
presence of IL-6 stimulation of TH17 cells.
Central mediator of fever and pain; promotion
of vasodilation and vascular permeability.
Activation of the complement system;
enhancement of phagocytosis by macrophages
(opsonin-mediated phagocytosis).
Perry, 2009), a great deal of interest has been centered upon the role of
microglia in schizophrenia (Bernstein et al., 2009; Monji et al., 2009).
Initial post-mortem immunohistochemical investigations have provided equivocal results with regards to microglia abnormalities in this
disorder: Whereas some studies report enhanced microglia cell
densities in the brains of schizophrenic patients (Bayer et al., 1999;
Radewicz et al., 2000; Garey, 2010), others do not find significant
microglia changes in affected individuals using post-mortem immunohistochemical techniques (e.g., Steiner et al., 2006,2008). More recent
approaches have used positron emission tomography (PET) to study the
role of microglia in schizophrenia. These studies have confirmed
enhanced microglia activation especially in temporolimbic gray matter
of schizophrenic patients (van Berckel et al., 2008; Doorduin et al.,
2009), suggesting that the disorder may indeed be associated with
significant microglia over-activation. However, there is an ongoing
debate as to whether such microglia abnormalities may be attributable
to medication effects rather than genuine neuroinflammatory processes
inherent to schizophrenic disease (Bernstein et al., 2009). This issue
awaits further validation by investigations of possible microglia
abnormalities in drug-naïve (or minimally medicated) first-episode
patient with schizophrenia.
There is an appreciable body of evidence suggesting that the
neuroinflammatory pathology in schizophrenia involves abnormal
astrocyte functions. Indeed, one well-established finding in this context
is the increase in serum and/or cerebrospinal fluid (CSF) levels of S100B,
a protein of the S-100 protein family that is involved in variety of
neuronal and glial signaling mechanisms (Rothermundt et al., 2009). In
the CNS, S100B is primarily produced by activated astroctyes, so that
elevated central levels of this protein likely reflect astroctye overactivation (Rothermundt et al., 2009). Interestingly, S100B exerts a
direct functional impact on microglia cells (Bianchi et al., 2011; Zhang et
al., 2011), so that this protein may provide an important molecular link
between abnormal astrocyte functions and the presumed microglia
activation in schizophrenic disease. It is also important to note that in
schizophrenic patients, S100B over-expression takes place in the
absence of astrogliosis (Bernstein et al., 2009; Rothermundt et al.,
2009). This suggests that the nature of such over-expression is related to
altered astroctye activity rather than density. The lack of overt
astrogliosis is in line with the neurodevelopmental hypothesis of
schizophrenia, suggesting that the majority of the histological and
neuroanatomical changes is unlikely to be the result of marked
neurodegeneration, but rather may reflect (progressive) changes in
100
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
neurodevelopmental processes (Weinberger, 1987; Fatemi & Folsom,
2009).
Increased CSF levels of pro-inflammatory cytokines such as IL-1β and
IL-6 (Garver et al., 2003; Söderlund et al., 2009) as well as up-regulated
cyclooxygenase (COX) expression (Das & Khan, 1998) have also been
noted in schizophrenic patients, providing additional support for the
hypothesis of activated central inflammatory responses in affected
individuals. Some reports further suggest that schizophrenia is associated with reduced potency to mount anti-inflammatory and immunosuppressive responses in the CNS, as supported by findings of reduced
gene and/or protein expression of sIL-1RA and TGF-β receptor (Vawter
et al., 1997; Toyooka et al., 2003). Consistent with this impression, Müller
et al. (1997a) demonstrated that the levels of the soluble IL-6 receptor
(sIL-6R) are increased in the CSF of schizophrenic patients. In contrast to
other soluble cytokine receptors such is sIL-1RA or sIL-2R, sIL-6R does
not inhibit IL-6 signaling, but instead enhances IL-6 functions by acting as
an agonist in combination with IL-6 (Knüpfer & Preiss, 2008). Taken
together, there seems to be a relative shift towards enhanced proinflammatory and blunted anti-inflammatory activity with regards to
secreted inflammatory factors in the CNS of schizophrenic patients. This
pattern readily contrasts the immunological profile described in the
periphery, where enhanced pro-inflammatory activity appears to concur
with increased release of anti-inflammatory and/or immunosuppressive
factors. However, it remains a matter of debate as to whether distinct
brain regions may be differentially affected by inflammatory processes in
schizophrenia, and current immunological research in schizophrenia has
not yet been able to provide any conclusive data that would support this
possibility. Additional research is thus clearly warranted to explore this
issue directly.
4. Sources of activated inflammatory responses in schizophrenia
may be indicative of the possibility that at least part of the reported
immune abnormalities in this disorder may have a genetic etiology.
This impression is also supported by the numerous reports of genetic
variations in specific cytokine genes and/or cytokine gene promoter
polymorphisms in individuals with schizophrenia. Schizophrenic
patients have repeatedly been shown to display allelic variants in IL-1
and IL-1RA (Katila et al., 1999; Zanardini et al., 2003; Papiol et al., 2005;
Xu & He; 2010), IL-6 (Sun et al., 2008; Paul-Samojedny et al. 2010), IL-10
(Bocchio Chiavetto et al., 2002; Yu et al., 2004; He et al., 2006), and
TNF-α (Boin et al., 2001; Schwab et al., 2003; Saviouk et al., 2005) genes
and/or promoters. It is likely that such genetic variants exert a functional
impact on cytokine protein networks in affected subjects because many
of the cytokine gene/promoter polymorphisms are known to directly
influence protein synthesis. For example, schizophrenic patients display
those IL-10 promoter variants more frequently which facilitate IL-10
gene transcription and protein synthesis (Bocchio Chiavetto et al.,
2002). This specific association thus fits well the report of enhanced
baseline peripheral IL-10 levels in schizophrenia (Maes et al., 2002).
Taken together, there is appreciable evidence to assume that cytokine
protein and/or gene expression abnormalities pertinent to the inflammatory response in schizophrenia may be accounted for, at least in part,
by the presence of allelic variants in immune-related genes.
It is also of note that genetic variants in immune-related genes may
significantly impact on the clinical efficacy of APD treatment. For
example, there is a remarkable pharmacogenetic relationship between
IL-1RA gene polymorphism and clinical improvement of negative
symptoms during antipsychotic treatment in patients with a first nonaffective psychotic episode (Mata et al., 2006). The clinical efficacy of
APDs has also been found to be modulated by polymorphisms in the
TNF-α gene (Zai et al., 2006) and other immune-related genes,
including human leukocyte antigens (HLA) (Lahdelma et al., 2001).
4.1. Genetic predisposition
4.2. Early-life immune priming
It has long been recognized that schizophrenia is a heritable
disorder that probably involves multiple genetic abnormalities with
relatively modest effects across large populations (Sullivan, 2005).
There have been tremendous efforts to identify potential schizophrenia susceptibility genes using single nucleotide polymorphisms
(SNPs) approaches, and such investigations have put forward a
number of genes that may be relevant for the genetic etiology of this
disorder, including neuregulin-1 (NRG-1), catechol-O-methyltransferase
(COMT), and disrupted in schizophrenia-1 (DISC-1) (Harrison &
Weinberger, 2005; Gogos & Gerber, 2006). However, many of these
genes have been identified and portrayed in relatively small populations, and recent research suggests that several of the presumed
candidate genetic factors do not reach significance in association studies
conducted in larger populations (Sanders et al., 2008; Nieratschker et al.,
2010).
More recently, genome-wide association studies (GWAS) have been
initiated with the aim of indentifying genetic variants which increase
susceptibility to schizophrenia in large populations (O'Donovan et al.,
2009). Interestingly, schizophrenia GWAS have consistently implicated
genetic variants in the major histocompatibility complex (MHC) on
chromosome 6 as common susceptibility factor for the disorder (Purcell
et al., 2009; Shi et al., 2009; Stefansson et al., 2009). In humans, this MHC
region contains 140 genes, most of which have known immune
functions (Kumánovics et al., 2003). Several other studies confirm the
importance of variants in immune-related genes in schizophrenia. For
example, recent schizophrenia GWAS pathway analyses show that
numerous signaling pathways involved in inflammation are consistently associated with schizophrenia in large genetic data sets (Jia et al.,
2010). Moreover, a genome-wide microarray study demonstrates that
an appreciable number of genes found to be down-regulated in the
superior temporal cortex of schizophrenic patients are closely associated with immune functions (Schmitt et al., 2011). These recent findings
A plethora of epidemiological studies in humans and experimental
work in animals emphasizes the critical impact of the early-life
environment in shaping postnatal physiological, emotional and behavioral functions. Stimulated by the seminal work of David Barker
conducted in the context of coronary heart disease (Dover, 2009), the
concept of “early-life programming of adult disease” is now well
accepted. This concept refers to the phenomenon whereby specific
environmental factors acting during sensitive prenatal or early postnatal
developmental periods can induce persistent changes in physiological,
emotional and behavioral functions throughout life (Bale et al., 2009;
Dover, 2009; Meyer et al., 2011). Accumulating evidence suggests that
such early-life programming also exists for the functional development of
the immune system (Merlot et al., 2008; Bilbo & Schwarz, 2009).
Perinatal exposure to infection and/or immune activation is one of the
prominent environmental factors with known impact on postnatal
immune functions (Bilbo & Schwarz, 2009). For example, prenatal
maternal exposure to the bacterial endotoxin lipopolysaccharide (LPS) or
the pro-inflammatory cytokine IL-6 in rats leads to enhanced microglial
densities and elevation of peripheral and central pro-inflammatory
cytokine levels in the offspring (Borrell et al., 2002; Samuelsson et al.,
2006; Romero et al., 2010). Such inflammatory changes can persist even
until adulthood (Borrell et al., 2002; Samuelsson et al., 2006; Romero et
al., 2010), suggesting that immune challenge early in life can permanently alter postnatal immune functions. Further to the precipitation of
overt immune dysfunctions, which may be evident even under basal
conditions, early-life exposure to infection and/or immune activation
may also induce sensitizing or preconditioning effects. In this scenario,
immunological exposure in early (prenatal or neonatal) life can cause the
organism to mount exacerbated reactions to subsequent immunological
or non-immunological challenges in later life (Bilbo & Schwarz, 2009;
Meyer et al., 2011).
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
Notably, early-life infection and/or immune activation not only
shapes the functional development of the immune system, but it also
elevates the risk of developing schizophrenia and related psychotic
disorders in later life (Bale et al., 2009; Brown & Derkits, 2010). One
prevalent hypothesis suggests that infection/inflammation-induced
disruption of fetal neurodevelopmental processes may predispose the
organisms to long-lasting changes in subsequent brain and behavioral
development, thereby increasing the risk of psychotic disturbances in
early adulthood (Gilmore & Jarskog, 1997; Meyer et al., 2009). This
hypothesis has been substantiated by numerous investigations in
experimental rodent models demonstrating the emergence of altered
fetal brain development (Meyer et al., 2008a; Vuillermot et al., 2010) and
multiple long-term brain and behavioral abnormalities relevant to
schizophrenia following prenatal exposure to infection and/or immune
activation (Meyer & Feldon, 2010). Recent molecular studies further
underscore the essential role of prenatal cytokine-associated inflammatory processes in mediating the effects of maternal infection on the
offspring: Blocking the actions of the pro-inflammatory cytokine IL-6 in
the pregnant maternal host by genetic or pharmacological interventions,
or genetically enforced over-expression of the anti-inflammatory
cytokine IL-10, prevents the long-term brain and behavioral consequences of prenatal viral-like immune activation in mice (Smith et al.,
2007; Meyer et al., 2008b). In addition to the suggested role of cytokine
alterations, several other immune factors such as complement and MHC I
or II proteins may be critical in mediating the effects of (prenatal)
inflammation in altering neurodevelopmental trajectories: These molecules are essential for normal brain development by regulating various
neurodevelopmental processes (Huh et al., 2000; Boulanger & Shatz,
2004; Boulanger, 2009; Shatz, 2009), and their expression is strongly
regulated by inflammatory stimuli such as cytokines (Boulanger et al.,
2001). Hence, abnormal expression of immune factors such as
complement and MHC proteins may be an essential molecular pathway
by which prenatal inflammation can induce changes in brain and
behavioral development.
In view of its concomitant impact on schizophrenia risk and immune
system development, it is intriguing to speculate that early-life immune
exposure may provide a developmental source of altered immune
functions in schizophrenia. Hence, inflammatory processes targeting
the fetal and/or neonatal brain may not only interfere with normal brain
development, but may further induce long-term changes in postnatal
immune functions. A similar conclusion has been drawn from a recent
microarray study suggesting that at least a subset of schizophrenic
patients may carry altered immune/chaperone gene signatures in the
prefrontal cortex that reflect long-term consequences of early-life
exposure to infection and/or immune challenge (Arion et al., 2007).
4.3. Impaired neuroendocrine feedback inhibition
Immunological functions are inherently linked to and modulated
by neuroendocrine systems, especially the hypothalamic–pituitary–
adrenal (HPA) axis (Rivest, 2010). Activation of the (innate) immune
system increases the activity of the HPA axis, a process that can be
mediated directly or indirectly through pro-inflammatory cytokines
(Dantzer et al., 2008; Rivest, 2010). Release of glucocorticoids
(cortisol in humans and primates, corticosterone in rodents) by the
adrenal cortex is the major hormonal output of the HPA axis. In
addition to their wide-ranging metabolic functions, glucocorticoids
are an essential part of the homeostatic control of the immune system,
where they potently suppress various immune functions in general,
and inflammatory responses in particular (Rhen & Cidlowski, 2005).
With regards to the latter, glucocorticoids have potent anti-inflammatory
properties by suppressing the production and/or secretion of proinflammatory molecules such as pro-inflammatory cytokines, prostaglandins, leukotrienes and COX-1/COX-2 (Rhen & Cidlowski, 2005).
Blunted neuroendocrine feedback inhibition of immune functions can
101
thus readily facilitate the persistence of inflammation once inflammatory
processes have been initiated (Raison & Miller, 2003).
Given this, impairments in the neuroendocrine regulation of
inflammation may provide another source of the abnormally enhanced
inflammatory responses in schizophrenia (Fig. 1). Indeed, there is an
appreciable body of evidence implicating insufficient glucocorticoid
signaling and/or glucocorticoid resistance in this disorder. Using the
dexamethasone suppression test, a test that is commonly used to
assesses glucocorticoid responsiveness, several studies report higher
rates of non-suppression in schizophrenia (Yeragani, 1990), indicating
that at least a sub-group of patients display impaired responsiveness to
glucocorticoids. It is of interest to note that such glucocorticoid
unresponsiveness is more prevalent in those schizophrenic patients
who show marked negative symptoms as compared to those patients
with modest negative symptomatology (Altamura et al., 1989;
McGauley et al., 1989). One implication is that impaired neuroendocrine
regulation of immune functions may contribute to abnormal inflammatory responses especially in those patients showing severe forms of
negative symptomatology.
5. Relevance of inflammatory processes
to distinct symptom classes of schizophrenia
In the context of neuropsychiatry, activated inflammatory processes
are by no means specific to schizophrenia, but have also been implicated
in other mental illnesses, especially major depression (Anisman et al.,
2002; Müller & Schwarz, 2007; Dantzer et al., 2008; Müller et al., 2009)
and bipolar disorder (Drexhage et al., 2010). This may not be
unprecedented, nor does it undermine the relevance of inflammatory
processes to schizophrenia, because the clinical features of schizophrenia,
especially those that are included in the category of negative/cognitive
symptoms, overlap significantly with affective, social and cognitive
dysfunctions typically implicated in depressive and bipolar disease
(Möller, 2007). Indeed, the clinical similarities between negative and
depressive symptoms on the one hand, and between negative and
cognitive symptoms on the other hand, may readily be appreciated in
view of their shared manifestations (Möller, 2007). For example, apathy,
anhedonia, and psychomotor retardation are common to negative
symptoms and depression, whereas reduced attention and poor
communication seem common to the negative/cognitive symptoms of
schizophrenia and major depression (Segrin, 2000; Eizenman et al.,
2003; Bell & Mishara, 2006; Harvey et al., 2006; Günther et al., 2011). It
is beyond the scope of this article to provide a discussion of the role of
activated inflammatory response systems in major depression and
bipolar disorder, so we would like to refer to those articles that have
discussed this issue in detail (Anisman et al., 2002; Müller & Schwarz,
2007; Dantzer et al., 2008; Müller et al., 2009).
In what follows, we go on to draw attention to the intriguing
possibility that activated inflammatory responses in schizophrenia
may be relevant especially for the pathogenesis and treatment of the
negative and cognitive symptoms. To this end, we integrate
experimental and clinical findings of the behavioral, cognitive and
neuronal effects of activated inflammatory systems, and we discuss
the recent progress in treating schizophrenic disease by antiinflammatory pharmacotherapy.
5.1. Negative symptoms
Pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α, have long
been recognized to play an essential role in the modulation of various
brain functions (Larson & Dunn, 2001; Anisman et al., 2002). One wellestablished finding is that enhanced peripheral and/or central proinflammatory cytokine signaling markedly impairs affective, emotional
and social functions (Dantzer et al., 2008). For example, peripheral
and/or central administration of pro-inflammatory cytokine releasing
agents robustly induces anhedonic behavior and social impairments
102
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
Fig. 1. Characteristics, sources, and neuronal consequences of activated inflammatory responses in schizophrenia. Abnormal expression of inflammatory genes in monocytes/macrophages
(M/M) facilitates the development of peripheral low-grade inflammation in patients with schizophrenia (represented by solid orange and green lines) as compared to healthy subjects
(represented by dashed orange and blue lines). Such peripheral low-grade inflammation seems to be characterized by fluctuations in abnormal pro- and anti-inflammatory activity,
whereby enhanced pro-inflammatory activity (orange lines) typically precedes the onset of increased anti-inflammatory activity (green lines). In schizophrenia, inflammatory responses
may follow processes of sensitization and thus may react more vigorously to the presence of specific environmental factors such as physical or psychological stress, or pathogen contact.
Stress and/or pathogen exposure in psychosis-prone subjects may lead to an over-activation of microglia (MG) cells, which in turn promote functional activation of astrocytes (AST).
Abnormally enhanced astroycte activity is accompanied by up-regulated S100B expression. In addition, activated astroctyes release a set of cytokines (primarily IL-6, IL-10, and TGF-β) that
stimulate the production of kynurenic acid (KYNA) by facilitating the enzymatic activity of tryptophan 2,3-dioxygenase (TDO) in astroctyes. KYNA blocks signaling at the NMDA receptor
(NMDA-R) and α7 nicotinic acetylcholine receptor (α7nAChR). On the other hand, activated MG secrete a set of pro-inflammatory cytokines (primarily IL-1β, IL-12, and TNF-α) that
stimulate the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), which in turn weakens the biosynthesis of serotonin (5-HT) and promotes the production of quinolinic acid (QUIN)
and 3-hydroxykynurenine (3-OHKY). QUIN and 3-OHKY are neurotoxic and may therefore contribute to inflammation-mediated neurotoxicity. Note that there is a mutual inhibitory effect
of IDO and TDO, so that their enzymatic activities are critically determined by the prevailing cytokine milieu. Abnormal HPA axis functions may further contribute to the development of
low-grade inflammation and sensitized inflammatory responses in schizophrenia. Under normal conditions, corticotropin-releasing hormone (CRH) released by the paraventricular
nucleus of the hypothalamus (PVN) stimulates secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland (PG), which in turn promotes the release of cortisol
(CORT) from the adrenal cortex (AC). CORT normally exerts fast feedback inhibition of HPA axis functions and suppresses pro-inflammatory activity by immune cells. These inhibitory
mechanisms are disrupted in patients with schizophrenia, so that impaired neuroendocrine regulation of immune functions may further facilitate the development of abnormally
enhanced pro-inflammatory responses in this disorder. Genetic variants in several immune-related genes and/or gene promoter regions (MHC, IL-1, IL-6, IL-10, and TNF) may provide a
genetic source for altered immune responses in schizophrenia; and prenatal immune priming induced by in-utero exposure to infection may provide a developmental source of long-term
immune abnormalities pertinent to schizophrenia.
(Anisman et al., 2002; Dantzer et al., 2008), both of which have been
consistently linked to the negative symptoms of schizophrenia (Möller,
2007; Tandon et al., 2009). Furthermore, peripheral inflammation
involving enhanced release of IL-6 has been associated with two other
hallmark features of negative symptoms, namely deficiency in sustained
attention (Holden et al., 2008) and psychomotor retardation (Brydon et
al., 2008).
One of the emerging neuroimmunological mechanisms linking
enhanced pro-inflammatory activity with the induction of affective,
emotional and social impairment involves alterations in the central
tryptophan metabolism (Müller & Schwarz, 2007). Tryptophan is an
essential amino acid needed for the biosynthesis of serotonin. As
discussed in detail elsewhere (Müller & Schwarz, 2007), enhanced proinflammatory actions in the CNS lead to increased tryptophan
degradation into kynurenine by indoleamine 2,3-dioxygenase (IDO),
thereby reducing the bioavailability of tryptophan for serotonin
synthesis (Fig. 1). Hence, increased pro-inflammatory actions in the
CNS can critically contribute to central serotonin deficiency. Besides its
involvement in depressive illness (Müller & Schwarz, 2007), serotonin
insufficiency has been suggested to play an important role in the
pathogenesis of negative symptoms of schizophrenia (Abi-Dargham et
al., 1997; Silver, 2004).
In view of the aforementioned behavioral and neuronal effects of
activated inflammatory responses, one would expect a positive
correlation between signs of peripheral and/or central inflammation
in schizophrenia and clinical measures of negative symptoms. Several
findings readily fulfill this expiation: First, there is an established
association between elevated S100B levels and persistent negative
symptoms as well as poor therapeutic response in patients with
schizophrenia (Rothermundt et al., 2004, 2009). Furthermore, concentrations of plasma IL-6 and IL-8 (Kim et al., 2000; Zhang et al., 2002) as
well as soluble markers indicative of blood brain barrier disruption
(Müller & Ackenheil, 1995) have been reported to positively correlate
with the severity of negative (but not positive) symptoms. These
findings have further been complemented by a study showing that
serum CRP levels positively correlate with the negative (but not
positive) symptoms in a subset of schizophrenic patients displaying
marked increases of this inflammatory marker in the periphery (Fan et
al., 2007b). However, it appears that this specific correlation cannot be
generalized to a broader sample of schizophrenic patients covering a
wider spectrum of peripheral CRP levels (Dickerson et al., 2007),
suggesting that the specific association between high CRP levels and
severe forms of negative symptoms is limited to those patients with
markedly high levels of this marker.
5.2. Cognitive symptoms
The impact of activated inflammatory response systems in schizophrenia may well be extended to disease-relevant cognitive impairments.
Indeed, there is a growing body of evidence highlighting a positive
correlation between the severity of cognitive deficits and enhanced levels
of inflammatory markers in schizophrenic patients, including IL-1β, IL-6,
TNF-α, CRP, and S100B (Dickerson et al., 2007; Pedersen et al., 2008; Liu et
al., 2010). The specificity of the cognitive effects induced by inflammatory
processes in schizophrenia remains to be further elucidated. However,
experimental studies in animals and correlative investigations in nonschizophrenic individuals suggest that the spectrum of inflammationmediated cognitive impairments may primarily affect domains of
executive functions, sustained attention and working memory (Marsland
et al., 2006; Holden et al., 2008; Cohen et al., 2011), all of which have been
implicated in schizophrenia (Elvevåg & Goldberg, 2000; Bowie & Harvey,
2006; Tandon et al., 2009). Molecular investigations in experimental
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
rodent models have also confirmed that pro-inflammatory cytokines can
exert appreciable influences on various forms of synaptic plasticity, which
is recognized to provide an important neuronal substrate for multiple
aspects of learning and memory (Bauer et al., 2007). It is therefore feasible
that altered pro-inflammatory activity may exert its cognitive effects by
modulating synaptic architecture and functions (McAfoose & Baune,
2009). Indeed, pro-inflammatory cytokines have been described to exert a
direct functional interaction with specific neurotransmitter systems and/
or or receptors (Schneider et al., 1998; Curran & O'Connor, 2001; Balschun
et al., 2004). Of particular interest in this context is the recently described
interaction between the IL-1β signaling system and the N-methyl-Daspartate (NMDA) receptor complex (Gardoni et al., 2011), the latter of
which is critically involved in numerous cognitive processes (Lynch, 2004;
Neill et al., 2010).
An alternative (but not mutually exclusive) neuronal mechanism by
which enhanced pro-inflammatory activity could affect cognitive
functions may again be related to changes in the central kynurenine
pathway (Fig. 1). More specifically, imbalances in the (local) astroctye/microglia cytokine milieu together with enhanced astroycte
functions can result in altered expression and/or activation of catalytic
enzymes involved in this pathway, eventually resulting in enhanced
production of kynurenic acid (KYNA) (Müller et al., 2009; Müller &
Schwarz, 2010; Wonodi & Schwarcz, 2010). KYNA is a potent
endogenous NMDA receptor antagonist acting at the glycine site of
the receptor (Wonodi and Schwarcz, 2010). Impaired glutamatergic
signaling at NMDA receptors has frequently been associated with
schizophrenia in general (Carlsson et al., 2001; Coyle et al., 2003; Javitt,
2007), and with the emergence of disease-relevant cognitive symptoms
in particular (Morgan et al., 2004; Lewis & Moghaddam, 2006; Yang &
Svensson, 2008). Moreover, enhanced production of KYNA (Nilsson et
al., 2005; Linderholm et al., in press) and associated changes in the
central kynurenine pathway (Condray et al., 2011; Sathyasaikumar et
al., in press) have been consistently documented in schizophrenic
patients. Experimental work in animals further shows that enhancement of KYNA disrupts a variety of schizophrenia-relevant cognitive
functions (Chess & Bucci, 2006; Chess et al., 2007; Akagbosu et al., in
press). Taken together, there is emerging evidence to support a model in
which enhanced pro-inflammatory activity can lead to cognitive
disturbances via inflammation-mediated modulation of the central
kynurenine pathway and subsequent impairments in NMDA receptormediated signaling (Müller, 2008; Wonodi & Schwarcz, 2010; Fig. 1).
Besides its impact on NMDA receptor signaling, KYNA also potently
inhibits cholinergic neurotransmission by blocking nicotinic acetylcholine receptors (nAChR), especially α7 nAChRs (Hilmas et al., 2001). Such
cholinergic effects are primarily induced at relatively low concentrations of KYNA (Hilmas et al., 2001; Wonodi & Schwarcz, 2010). In
keeping with the suggested contribution of impaired nAChR signaling to
cognitive symptoms of schizophrenia (Martin & Freedman, 2007),
inhibition of nAChR by KYNA over-production may provide an
additional neuroimmunological link between activated central inflammatory responses and emergence of cognitive impairments in this
disorder (Müller & Schwarz, 2010; Wonodi & Schwarcz, 2010; Fig. 1).
5.3. Positive symptoms
In addition to its presumed contribution to negative and cognitive
symptoms, enhanced pro-inflammatory activity could also play a role in
the emergence of positive symptoms. Of special interest in this context
are the stimulatory effects of pro-inflammatory cytokines on DA and
noradrenalin (NA) synthesis and release (Zalcman et al., 1994; Hayley et
al., 2002; Dunn, 2006). Enhanced DA and NA production in the event of
enhanced pro-inflammatory activity seems to involve changes in the
enzymatic activity of tyrosine hydroxylase (TH) (Abreu et al., 1994), the
rate-limiting enzyme of endogenous DA and NA synthesis in-vivo
(Bacopoulos & Bhatnagar, 1977). Enhanced DA and NA activity
(especially in mesolimbic structures) have been repeatedly implicated
103
in the emergence of positive psychotic symptoms through neuropsychological mechanisms that affect the salience of internal and/or
external representations and induce states of hypervigilance, respectively (Gray et al., 1991; Kapur, 2003; Yamamoto & Hornykiewicz,
2004). Hence, there would be a feasible theoretical framework
implicating a potential role of enhanced pro-inflammatory activity in
the emergence of positive symptoms of schizophrenia. However, with
the exception of a limited number of studies (Zhang et al., 2002; Kim et
al., 2009), the majority of investigations does not find a strict positive
correlation between the severity of positive symptoms of schizophrenia
and enhanced levels of prototypical pro-inflammatory cytokines such as
IL-1β, IL-6 and TNF-α (e.g., Kim et al., 2000; Zhang et al., 2005, 2009). A
conclusion as to whether or not enhanced pro-inflammatory activity
may play an essential role in the precipitation of positive symptoms thus
seems premature at present. Further research is clearly warranted to
address this issue in more detail.
6. Immunomodulatory effects of antipsychotic drugs
and anti-inflammatory treatment strategies in schizophrenia
6.1. Cytokine effects of antipsychotic drugs
Numerous APDs are known to exert modulatory effects on immune
functions in general, and on peripheral cytokine networks in particular.
This issue has been thoroughly discussed elsewhere (Pollmächer et al.,
2000; Drzyzga et al., 2006). For the present purpose, we would like to
draw attention to the anti-inflammatory effects of APDs: A large body of
evidence indicates that (long-term) treatment with APDs potently
enhance anti-inflammatory activity as indexed by the augmentation of
peripheral production of sIL-1RA, sIL-2R and IL-10 (Maes et al., 1996,
1997; Müller et al., 1997b; Song et al., 2000; Cazzullo et al., 2002; Sirota et
al., 2005; Sugino et al., 2009), and by the concomitant reduction of proinflammatory markers such as IL-1β, IL-6 sIL-6R, and TNF-α (Müller et al.,
1997b; Kim et al., 2009; Song et al., 2009; Sugino et al., 2009).
Interestingly, it seems that the class of atypical (second-generation)
APDs such as clozapine may have more pronounced effects on enhancing
anti-inflammatory cytokine signaling compared to the class of typical
(first-generation) APDs (reviewed in Pollmächer et al., 2000; Drzyzga et
al., 2006). It has been further suggested that the relative capacity of APDs
to normalize pro-inflammatory immune changes may be an important
contributing factor determining the clinical efficacy of APDs in the
symptomatological treatment of schizophrenic disease (Müller &
Schwarz, 2008, 2010). Consistent with this hypothesis, it has been show
that those schizophrenic patients who are resistant to APD-induced
behavioral improvement display persistently high IL-6 levels, and that
such immune abnormalities in treatment-resistant schizophrenic patients
cannot be restored by APDs either (Lin et al., 1998; Zhang et al., 2005).
6.2. Anti-inflammatory treatment strategies
In view of the apparent involvement of inflammatory processes, the
use of compounds with primary anti-inflammatory properties has
received increasing attention in the pharmacotherapy of schizophrenia.
Importantly, recent clinical trials of anti-inflammatory add-on therapy in
schizophrenia provide promising results by showing superior beneficial
treatment effects when standard APDs are co-administered with antiinflammatory compounds, as compared with treatment outcomes using
APDs alone. As summarized in Table 2, two main classes of antiinflammatory drugs have been tested as adjunctive medication in
schizophrenia, namely the tetracycline antibiotic minocycline (Miyaoka
et al., 2008; Levkovitz et al., 2010) and non-steroidal anti-inflammatory
drugs (NSAIDs), including the mixed COX-1/2 inhibitor acetylsalicylic
acid (Laan et al., 2010) and the selective COX-2 inhibitor celecoxib
(Müller et al., 2002, 2005; Rapaport et al., 2005; Akhondzadeh et al.,
2007; Müller et al., 2010). It is also worth emphasizing that in addition to
the use of primary anti-inflammatory agents, compounds with potent
104
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
Table 2
Anti-inflammatory treatment strategies in schizophrenia. The table outlines the different treatment strategies used in clinical trials of anti-inflammatory add-on therapy in
schizophrenia. The main cellular and molecular targets of each class of anti-inflammatory drugs are also summarized. Symbol (+) denotes the number of clinical trials showing
superior beneficial treatment effects of combined anti-inflammatory and antipsychotic drug administration relative to antipsychotic drug administration alone; symbol (−) denotes
the number of clinical trials showing no superior treatment effects of combined anti-inflammatory and antipsychotic drug administration relative to antipsychotic drug
administration alone.
Drug
Class
Main anti-inflammatory actions
Effect in schizophrenia
References
Acetylsalicylic acid
(Aspirin)
Mixed COX-1/2 inhibitor
(+)
Laan et al., 2010
Celecoxib
Selective COX-2 inhibitor
–Irreversibly inactivates COX-1 and attenuates
the enzymatic activity of COX-2
–Blocks nuclear factor-kappa B (NF-κB) signaling
–Inhibits the production of prostanoids
(prostaglandins, prostacyclin, and thromboxanes)
and pro-inflammatory cytokines
–Selectively blocks the enzymatic activity of
COX-2 at sites of inflammation
–Inhibits nuclear
Factor-kappa B (NF-κB) signaling
–Inhibits the production of prostanoids
(prostaglandins, prostacyclin, and thromboxanes)
and pro-inflammatory cytokines
–Bacteriostatic effects limiting the growth of bacteria
–Inhibition of matrixmetaloproteinase-9
–Inhibits the production of pro-inflammatory
cytokines and activation of peripheral as well as
central immunocompetent cells, including T cells,
macrophages, and microglia
(+)
Müller et al., 2002
(+)
(+)
(+)
(−)
Müller et al., 2005
Müller et al., 2010
Akhondzadeh et al., 2007
Rapaport et al., 2005
(+)
(+)
Miyaoka et al., 2008
Levkovitz et al., 2010
Minocycline
Tetracycline broad-spectrum antibiotic
anti-oxidant properties (and additional anti-inflammatory activity) such
as N-acetyl-cysteine have also been subject of recent interest in the
pharmacological treatment of schizophrenia (Lavoie et al., 2008; Bulut et
al., 2009). The rationale and biological basis of anti-oxidant therapies in
schizophrenia have recently been discussed elsewhere (Do et al., 2009;
Bitanihirwe & Woo, 2011).
given in conjunction with standard atypical APD in the early-phase of
schizophrenia, demonstrating that such anti-inflammatory add-on
therapy has selective effects in improving negative symptoms (Müller
et al., 2010). Together, these findings suggest that anti-inflammatory
adjunctive therapies, at least those which use COX-2 inhibitors or the
broad-spectrum antibiotic minocylcine, may have potent beneficial
effects on negative/cognitive symptoms of schizophrenia.
6.3. Efficacy of anti-inflammatory
treatment against negative/cognitive symptoms
6.4. Anti-inflammatory treatment and disease progression
The clinical data thus far available highlight that in addition to their
potential beneficial influence on positive symptoms (Akhondzadeh et
al., 2007; Laan et al., 2010), anti-inflammatory add-on therapies in
schizophrenia are readily effective in the treatment of negative and
cognitive symptoms. Indeed, in a recent double-blind, randomized,
placebo-controlled study in the early-phase of schizophrenia, minocycline administration in conjunction with standard APDs has been shown
to significantly improve negative and cognitive symptoms (Levkovitz et
al., 2010). The pro-cognitive effects of minocycline treatment were
primarily seen in improvements of executive dysfunctions (Levkovitz et
al., 2010). Importantly, combined minocycline and APD treatment was
well tolerated and showed superior treatment effects relative to
treatment outcomes using APDs alone. However, it needs to be
emphasized that this clinical trial using minocycline add-on therapy
did not specifically address potential beneficial effects against positive
symptoms (Levkovitz et al., 2010), so that this anti-inflammatory
approach still awaits further validation with regards to its specificity
against distinct symptoms classes of schizophrenia.
Add-on therapies using COX-2 inhibitors in schizophrenia have also
provided clear evidence for a therapeutic efficiency of this antiinflammatory agent in the treatment of schizophrenic symptoms,
including negative and cognitive symptoms (Table 2): In the first clinical
trial conducted in patients with acute exacerbation of schizophrenic
psychosis, the COX-2 inhibitor celecoxib given in conjunction with the
atypical APD risperidone has been shown to be superior to risperidone
treatment alone in improving total Positive and Negative Syndrome
Scale (PANSS) scores (Müller et al., 2002). Such COX-2 inhibitor add-on
therapy has subsequently been reported to exert appreciable beneficial
effects on cognitive symptoms (Müller et al., 2005). Even more
compelling are the findings of a recent randomized, double-blind,
placebo-controlled clinical trial using the COX-2 inhibitor celecoxib
Recent data obtained from clinical trials using COX-2 inhibitor
treatment in schizophrenia indicate that the efficacy of such antiinflammatory pharmacotherapy to improve schizophrenic symptoms
may be critically influenced by factors pertinent to the disease
progression. In randomized, double-blind, placebo-controlled clinical
trials using celecoxib given in conjunction with atypical APDs, superior
beneficial treatment effects are obtained especially when such antiinflammatory add-on therapy is initiated in the early-phase of
schizophrenia as opposed to later chronic stages (Müller et al., 2010;
Müller & Schwarz, 2010). In fact, such anti-inflammatory pharmacotherapy may exert no superior effects in the symptomatological
treatment of schizophrenia when implemented in patients with a long
duration of disease (Rapaport et al., 2005).
These findings raise the possibility that the nature and/or severity of
activated inflammatory responses in schizophrenia may critically change
as a function of disease progression, so that primary anti-inflammatory
strategies may be particularly efficient when targeting those immune
abnormalities that are characteristic of the early stage of schizophrenia.
There is no doubt that our understanding of the precise immune
signature in the early-phase of schizophrenia is far from complete.
However, from the findings obtained in clinical trials of COX-2 inhibitor
adjuvant therapy (Müller et al., 2010; Müller & Schwarz, 2010), one may
speculate on a model in which enhanced pro-inflammatory activity may
be particularly prominent in the early-phase of schizophrenic disease
(Fig. 2). This impression would be compatible with the (limited amount
of) data indicating that enhanced pro-inflammatory activity precedes
altered anti-inflammatory activity in schizophrenia, so that the former is
readily noticeable in drug-naïve first-episode schizophrenic patients
(O'Donnell et al., 1996; Theodoropoulou et al., 2001; Song et al., 2009;
Reale et al., 2011). It is of note that patients with schizophrenia frequently
report phases of stress in the proximity of or during the transition to full-
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
Fig. 2. Inflammatory responses and disease progression in schizophrenia. The figure
provides a hypothetical model illustrating potential relationships between temporal
changes in inflammatory responses and disease progression in schizophrenia. (a) Increased
pro-inflammatory activity (represented by solid orange lines) may be particularly
prominent in the early stage of schizophrenic disease, including the (initial) prodromal
phase and onset of full-blown psychotic episodes. The subsequent enhancement in antiinflammatory activity (represented by straight green lines) may provide a compensatory
response to the initial pro-inflammatory stimulus and may contribute to the resolution of
psychotic episodes and abnormally enhanced pro-inflammatory activity. The enhancement
of anti-inflammatory activity may partly be driven by endogenous response mechanisms,
and partly by the anti-inflammatory effects of antipsychotic drug treatment (not shown).
(b) Pharmacologically induced enhancement of anti-inflammatory activity by administration of primary anti-inflammatory agents during the early phase of schizophrenic disease
may attenuate gradual increases in pro-inflammatory activity and progression into fullblown psychotic disease. (c) Reduced potency to mount anti-inflammatory responses
(during the early phase of schizophrenic disease) may facilitate the gradual elevation of proinflammatory activity and may increase symptom severity and duration.
blown psychosis (Phillips et al., 2006), and exposure to physical or
psychological stressors is well known to enhance the production and
release of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α (GarcíaBueno et al., 2008). Psychosocial and/or physical tress in the early-phase
of schizophrenic disease may therefore readily contribute to the
enhancement of pro-inflammatory activity as reported by several studies
(O'Donnell et al., 1996; Theodoropoulou et al., 2001; Song et al., 2009;
Reale et al., 2011). Whatever the precise source of enhanced proinflammatory activity, the presence of such immune imbalances in the
early-phase of schizophrenia may explain as to why anti-inflammatory
strategies (at least those which are based on COX-2 inhibition) may be
particularly efficient in improving schizophrenic symptoms when
implemented at early stages of the disease (Fig. 2).
6.5. Should anti-inflammatory agents be used for preventive reasons?
There is increasing interest in prospectively identifying psychosisprone subjects when they are in the prodromal phase of the disorder.
105
The (initial) prodromal phase of schizophrenia refers to a muted form of
psychosis-related behavior that precedes the onset of full-blown
schizophrenic disorder (Klosterkötter et al., 2001). Prodromal symptoms appear to involve numerous but relative subtle emotional, social,
and cognitive abnormalities, and may further involve attenuated forms
of positive symptoms (Larson et al., 2010). It has been suggested that
early pharmacological treatment during the prodromal phase may
prevent or delay the subsequent emergence of a full-blown psychotic
episode by attenuating or even halting the progression of the underlying
pathology (McGlashan, 1996; Yung & McGorry, 1996). The underlying
rationale is based on the hypothesis that the longer a psychotic state is
left untreated, the more severe the long-term psychopathological
outcome is likely to be (Perkins et al., 2005). For this reason, chronic
administration of APDs to peri-adolescent and/or adolescent subjects
with prodromal symptoms has recently been introduced as preventive
treatment of schizophrenia (McGlashan et al., 2003; Woods et al., 2003;
McGlashan et al., 2006).
In view of the beneficial clinical effects of anti-inflammatory
treatment in the early-phase of schizophrenia (Müller et al., 2010), it
is interesting to ask whether administration of compounds with primary
anti-inflammatory properties could exert preventive effects against the
development of full-blown schizophrenic disease. An answer to this
question would be far from conclusive and, as a matter of fact, would
primarily be based on speculations. However, it is at least theoretically
feasible that in the event of enhanced pro-inflammatory activity, early
anti-inflammatory interventions in psychosis-prone subjects may
indeed be coupled with favorable long-term outcomes. As described
in Section 3.2, schizophrenia seems associated with reduced potency to
mount anti-inflammatory and immunosuppressive responses in the
CNS. Functional deficiency in anti-inflammatory/immunosuppressive
homeostatic control systems in the brain may have detrimental longterm consequences on brain and behavioral functions: If initially
induced, inflammatory stimuli may not be sufficiently counteracted by
appropriate anti-inflammatory reactions, and this may in turn facilitate
the development of persistent and presumably detrimental effects of
neuroinflammation on psychopathological and neuropathological
symptoms (Fig. 2).
Recent advances in brain imaging techniques have emphasized the
importance of progressive brain changes that occur during and
subsequent to the onset of full-blown psychosis (Hulshoff Pol & Kahn,
2008; Wood et al., 2008). The data thus far available suggest that such
progressive brain changes involve a marked loss of gray matter volume
especially during the adolescent stage of life and resemble an
exaggeration of gray matter reduction occurring as a result of normal
adult development (Hulshoff Pol & Kahn, 2008; Wood et al., 2008). Even
though the underlying molecular and cellular mechanisms remain to be
identified, it has been suggested that enhanced pro-inflammatory
activity in general, and microglia over-activation in particular, may play
a role in precipitating such progressive brain changes in schizophrenia
(van Berckel et al., 2008; Meyer et al., 2011).
Besides numerous other effects (Block et al., 2007), sustained
neuroinflammation readily facilitates the enzymatic activity of IDO,
and enzyme involved in the central kynurenine pathway (Müller et al.,
2009; Müller & Schwarz, 2010; Wonodi & Schwarcz, 2010). Enhanced
IDO activity leads to elevated production of quinolinic acid (QUIN) and
3-hydroxykynurenine (3-OHKY), both of which have potent neurotoxic
properties. Interestingly, a recent study by Condray et al. (2011) has
confirmed enhanced levels of 3-OHKY in drug-naïve first-episode
schizophrenic patients. The authors went on to show that following
APD treatment, the levels of 3-OHKY predicted clinical improvement in
as much as the lowest concentrations of 3-OHKY were associated with
the greatest improvement in symptoms (Condray et al., 2011). In view
of the neurotxic effects of 3-OHKY, it will be highly relevant to further
explore whether increased levels of 3-OHKY and other inflammationassociated factors may contribute to volumetric gray matter loss
occurring during and subsequent to the onset of full-blown psychosis.
106
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
If so, early anti-inflammatory interventions may indeed hold promise
for attenuating unfavorable neuropathological and psychopathological
outcomes in the disease progression of schizophrenia.
7. Conclusions
A large number of serologic and genetic studies support the presence
of activated peripheral and central inflammatory responses in schizophrenia. Such inflammatory processes seem to be influenced by a number
of environmental and genetic predisposition factors, and they may
critically depend on and contribute to the progressive nature of
schizophrenic disease. There is also appreciable evidence to suggest that
activated inflammatory responses can undermine disease-relevant
affective, emotional, social, and cognitive functions, so that inflammatory
processes may be particularly relevant for the precipitation of negative
and cognitive symptoms of schizophrenia. Against this background, antiinflammatory therapies in schizophrenia appear to be a promising
approach to improve such dysfunctions, and the extension of antiinflammatory therapies to the early stages of schizophrenia seems
feasible.
The available neuroimmunological and clinical data leave many
questions unanswered, especially with regards to the precise cellular
and molecular mechanisms underlying the beneficial therapeutic effects
of anti-inflammatory drugs in schizophrenia. However, these data
readily provide testable hypotheses, given the fact that the cellular and
molecular effects of most currently available anti-inflammatory drugs
are relatively well described. Animal models of schizophrenia, particularly those which recapitulate inflammatory components of the disorder,
may further help to identify the relevant neuroimmunological mechanisms pertinent to the beneficial clinical effects of anti-inflammatory
therapies in schizophrenia. Given the limited efficacy of currently
available APDs to ameliorate negative and cognitive symptoms, the
further exploration of inflammatory mechanisms and anti-inflammatory
strategies may open fruitful avenues for a better treatment of symptoms
undermining affective, emotional, social and cognitive functions relevant
for schizophrenic disease.
Disclosure
The authors declare that they have no conflicts of interest to
disclose. The founder of the present article (European Union's Seventh
Framework Programme (FP7/2007-2011) under grant agreement no.
259679) had no role in the preparation of the manuscript and in the
decision to publish it.
References
Abi-Dargham, A., Laruelle, M., Aghajanian, G. K., Charney, D., & Krystal, J. (1997). The
role of serotonin in the pathophysiology and treatment of schizophrenia. J
Neuropsychiatry Clin Neurosci 9, 1–17.
Abreu, P., Llorente, E., Hernández, M. M., & González, M. C. (1994). Interleukin-1 beta
stimulates tyrosine hydroxylase activity in the median eminence. Neuroreport 5,
1356–1358.
Akagbosu, C. O., Evans, G. C., Gulick, D., Suckow, R. F., & Bucci, D. J. (in press). Exposure to
kynurenic acid during adolescence produces memory deficits in adulthood.
Schizophr Bull, (Epub ahead of print [PMID: 21172906]).
Akhondzadeh, S., Tabatabaee, M., Amini, H., Ahmadi Abhari, S. A., Abbasi, S. H., &
Behnam, B. (2007). Celecoxib as adjunctive therapy in schizophrenia: A doubleblind, randomized and placebo-controlled trial. Schizophr Res 90, 179–185.
Akiyama, K. (1999). Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor
antagonist in schizophrenia before and during neuroleptic administration. Schizophr
Res 37, 97–106.
Altamura, C., Guercetti, G., & Percudani, M. (1989). Dexamethasone suppression test in
positive and negative schizophrenia. Psychiatry Res 30, 69–75.
Anisman, H., Kokkinidis, L., & Merali, Z. (2002). Further evidence for the depressive
effects of cytokines: Anhedonia and neurochemical changes. Brain Behav Immun 16,
544–556.
Arion, D., Unger, T., Lewis, D. A., Levitt, P., & Mirnics, K. (2007). Molecular evidence for
increased expression of genes related to immune and chaperone function in the
prefrontal cortex in schizophrenia. Biol Psychiatry 62, 711–721.
Bacopoulos, N. G., & Bhatnagar, R. K. (1977). Correlation between tyrosine hydroxylase
activity and catecholamine concentration or turnover in brain regions. J Neurochem
29, 639–643.
Bale, T. L., Baram, T. Z., Brown, A. S., Goldstein, J. M., Insel, T. R., McCarthy, M. M., et al.
(2009). Early life programming and neurodevelopmental disorders. Biol Psychiatry
68, 314–319.
Balschun, D., Wetzel, W., Del Rey, A., Pitossi, F., Schneider, H., Zuschratter, W., &
Besedovsky, H. O. (2004). Interleukin-6: A cytokine to forget. FASEB J 18, 1788–1790.
Barak, V., Barak, Y., Levine, J., Nisman, B., & Roisman, I. (1995). Changes in interleukin-1
beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic
patients. J Basic Clin Physiol Pharmacol 6, 61–69.
Bauer, S., Kerr, B. J., & Patterson, P. H. (2007). The neuropoietic cytokine family in
development, plasticity, disease and injury. Nat Rev Neurosci 8, 221–232.
Bayer, T. A., Buslei, R., Havas, L., & Falkai, P. (1999). Evidence for activation of microglia
in patients with psychiatric illnesses. Neurosci Lett 271, 126–128.
Bell, M. D., & Mishara, A. L. (2006). Does negative symptom change relate to neurocognitive
change in schizophrenia? Implications for targeted treatments. Schizophr Res 81,
17–27.
Benes, F. M., & Berretta, S. (2001). GABAergic interneurons: Implications for understanding
schizophrenia and bipolar disorder. Neuropsychopharmacology 25, 1–27.
Bernstein, H. G., Steiner, J., & Bogerts, B. (2009). Glial cells in schizophrenia:
Pathophysiological significance and possible consequences for therapy. Expert
Rev Neurother 9, 1059–1071.
Bianchi, R., Kastrisianaki, E., Giambanco, I., & Donato, R. (2011). S100B protein
stimulates microglia migration via RAGE-dependent up-regulation of chemokine
expression and release. J Biol Chem 286, 7214–7226.
Bilbo, S. D., & Schwarz, J. M. (2009). Early-life programming of later-life brain and
behavior: A critical role for the immune system. Front Behav Neurosci 3, 14.
Bitanihirwe, B. K., & Woo, T. U. (2011). Oxidative stress in schizophrenia: An integrated
approach. Neurosci Biobehav Rev 35, 878–893.
Block, M. L., Zecca, L., & Hong, J. S. (2007). Microglia-mediated neurotoxicity:
Uncovering the molecular mechanisms. Nat Rev Neurosci 8, 57–69.
Bocchio Chiavetto, L., Boin, F., Zanardini, R., Popoli, M., Michelato, A., Bignotti, S., et al.
(2002). Association between promoter polymorphic haplotypes of interleukin-10
gene and schizophrenia. Biol Psychiatry 51, 480–484.
Boin, F., Zanardini, R., Pioli, R., Altamura, C. A., Maes, M., & Gennarelli, M. (2001).
Association between -G308A tumor necrosis factor alpha gene polymorphism and
schizophrenia. Mol Psychiatry 6, 79–82.
Borrell, J., Vela, J. M., Arévalo-Martin, A., Molina-Holgado, E., & Guaza, C. (2002).
Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications
for the etiopathogenesis of schizophrenia. Neuropsychopharmacology 26, 204–215.
Boulanger, L. M. (2009). Immune proteins in brain development and synaptic plasticity.
Neuron 64, 93–109.
Boulanger, L. M., Huh, G. S., & Shatz, C. J. (2001). Neuronal plasticity and cellular
immunity: Shared molecular mechanisms. Curr Opin Neurobiol 11, 568–578.
Boulanger, L. M., & Shatz, C. J. (2004). Immune signalling in neural development,
synaptic plasticity and disease. Nat Rev Neurosci 5, 521–531.
Bowie, C. R., & Harvey, P. D. (2006). Treatment of cognitive deficits in schizophrenia.
Curr Opin Investig Drugs 7, 608–613.
Bradley, J. R. (2008). TNF-mediated inflammatory disease. J Pathol 214, 149–160.
Bresee, C., & Rapaport, M. H. (2009). Persistently increased serum soluble interleukin-2
receptors in continuously ill patients with schizophrenia. Int J Neuropsychopharmacol
12, 861–865.
Briand, J. P., & Muller, S. (2010). Emerging peptide therapeutics for inflammatory
autoimmune diseases. Curr Pharm Des 16, 1136–1142.
Brown, A. S., & Derkits, E. J. (2010). Prenatal infection and schizophrenia: A review of
epidemiologic and translational studies. Am J Psychiatry 167, 261–280.
Brydon, L., Harrison, N. A., Walker, C., Steptoe, A., & Critchley, H. D. (2008). Peripheral
inflammation is associated with altered substantia nigra activity and psychomotor
slowing in humans. Biol Psychiatry 63, 1022–1029.
Bulut, M., Savas, H. A., Altindag, A., Virit, O., & Dalkilic, A. (2009). Beneficial effects of Nacetylcysteine in treatment resistant schizophrenia. World J Biol Psychiatry 10,
626–628.
Carlsson, A., Waters, N., Holm-Waters, S., Tedroff, J., Nilsson, M., & Carlsson, M. L.
(2001). Interactions between monoamines, glutamate, and GABA in schizophrenia:
New evidence. Annu Rev Pharmacol Toxicol 41, 237–260.
Cazzullo, C. L., Sacchetti, E., Galluzzo, A., Panariello, A., Adorni, A., Pegoraro, M., et al.
(2002). Cytokine profiles in schizophrenic patients treated with risperidone: A 3month follow-up study. Prog Neuropsychopharmacol Biol Psychiatry 26, 33–39.
Chess, A. C., & Bucci, D. J. (2006). Increased concentration of cerebral kynurenic acid alters
stimulus processing and conditioned responding. Behav Brain Res 170, 326–332.
Chess, A. C., Simoni, M. K., Alling, T. E., & Bucci, D. J. (2007). Elevations of endogenous
kynurenic acid produce spatial working memory deficits. Schizophr Bull 33,
797–804.
Coelho, F. M., Reis, H. J., Nicolato, R., Romano-Silva, M. A., Teixeira, M. M., Bauer, M. E., &
Teixeira, A. L. (2008). Increased serum levels of inflammatory markers in chronic
institutionalized patients with schizophrenia. Neuroimmunomodulation 15,
140–144.
Cohen, R. A., de la Monte, S., Gongvatana, A., Ombao, H., Gonzalez, B., Devlin, K. N., et al.
(2011). Plasma cytokine concentrations associated with HIV/hepatitis C coinfection
are related to attention, executive and psychomotor functioning. J Neuroimmunol
233, 204–210.
Condray, R., Dougherty, G. G., Keshavan, M. S., Reddy, R. D., Haas, G. L., Montrose, D. M.,
et al. (2011). 3-Hydroxykynurenine and clinical symptoms in first-episode
neuroleptic-naive patients with schizophrenia. Int J Neuropsychopharmacol 14,
756–767.
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
Coyle, J. T., Tsai, G., & Goff, D. (2003). Converging evidence of NMDA receptor hypofunction
in the pathophysiology of schizophrenia. Ann N Y Acad Sci 1003, 318–327.
Curfs, J. H., Meis, J. F., & Hoogkamp-Korstanje, J. A. (1997). A primer on cytokines:
Sources, receptors, effects, and inducers. Clin Microbiol Rev 10, 742–780.
Curran, B., & O'Connor, J. J. (2001). The pro-inflammatory cytokine interleukin-18
impairs long-term potentiation and NMDA receptor-mediated transmission in the
rat hippocampus in vitro. Neuroscience 108, 83–90.
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From
inflammation to sickness and depression: when the immune system subjugates the
brain. Nat Rev Neurosci 9, 46–56.
Das, I., & Khan, N. S. (1998). Increased arachidonic acid induced platelet chemiluminescence indicates cyclooxygenase overactivity in schizophrenic subjects. Prostaglandins Leukot Essent Fatty Acids 58, 165–168.
DeLisi, L. E. (1996). Is there a viral or immune dysfunction etiology to schizophrenia?
Re-evaluation a decade later. Schizophr Res 22, 1–4.
DeLisi, L. E., & Wyatt, R. J. (1982). Abnormal immune regulation in schizophrenic
patients. Psychopharmacol Bull 18, 158–163.
Dickerson, F., Stallings, C., Origoni, A., Boronow, J., & Yolken, R. (2007). C-reactive protein is
associated with the severity of cognitive impairment but not of psychiatric symptoms
in individuals with schizophrenia. Schizophr Res 93, 261–265.
Do, K. Q., Cabungcal, J. H., Frank, A., Steullet, P., & Cuenod, M. (2009). Redox dysregulation,
neurodevelopment, and schizophrenia. Curr Opin Neurobiol 19, 220–230.
Doorduin, J., de Vries, E. F., Willemsen, A. T., de Groot, J. C., Dierckx, R. A., & Klein, H. C.
(2009). Neuroinflammation in schizophrenia-related psychosis: A PET study. J Nucl
Med 50, 1801–1807.
Dover, G. J. (2009). The Barker hypothesis: How pediatricians will diagnose and prevent
common adult-onset diseases. Trans Am Clin Climatol Assoc 120, 199–207.
Drexhage, R. C., Hoogenboezem, T. A., Cohen, D., Versnel, M. A., Nolen, W. A., van
Beveren, N. J., et al. (2011). An activated set point of T-cell and monocyte
inflammatory networks in recent-onset schizophrenia patients involves both proand anti-inflammatory forces. Int J Neuropsychopharmacol 14, 746–755.
Drexhage, R. C., Knijff, E. M., Padmos, R. C., Heul-Nieuwenhuijzen, L., Beumer, W.,
Versnel, M. A., & Drexhage, H. A. (2010). The mononuclear phagocyte system and
its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert
Rev Neurother 10, 59–76.
Drzyzga, L., Obuchowicz, E., Marcinowska, A., & Herman, Z. S. (2006). Cytokines in
schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun 20, 532–545.
Dunn, A. J. (2006). Effects of cytokines and infections on brain neurochemistry. Clin
Neurosci Res 6, 52–68.
Eizenman, M., Yu, L. H., Grupp, L., Eizenman, E., Ellenbogen, M., Gemar, M., & Levitan, R. D.
(2003). A naturalistic visual scanning approach to assess selective attention in major
depressive disorder. Psychiatry Res 118, 117–128.
Elvevåg, B., & Goldberg, T. E. (2000). Cognitive impairment in schizophrenia is the core
of the disorder. Crit Rev Neurobiol 14, 1–21.
Fan, X., Goff, D. C., & Henderson, D. C. (2007a). Inflammation and schizophrenia. Expert
Rev Neurother 7, 789–796.
Fan, X., Pristach, C., Liu, E. Y., Freudenreich, O., Henderson, D. C., & Goff, D. C. (2007b).
Elevated serum levels of C-reactive protein are associated with more severe
psychopathology in a subgroup of patients with schizophrenia. Psychiatry Res 149,
267–271.
Fan, X., Liu, E. Y., Freudenreich, O., Park, J. H., Liu, D., Wang, J., et al. (2010). Higher white
blood cell counts are associated with an increased risk for metabolic syndrome and
more severe psychopathology in non-diabetic patients with schizophrenia.
Schizophr Res 118, 211–217.
Fatemi, S. H., & Folsom, T. D. (2009). The neurodevelopmental hypothesis of
schizophrenia, revisited. Schizophr Bull 35, 528–548.
Gabay, C., Lamacchia, C., & Palmer, G. (2010). IL-1 pathways in inflammation and
human diseases. Nat Rev Rheumatol 6, 232–241.
Gallin, J. I., Snyderman, R., Fearon, D. T., Haynes, B. F., & Nathan, C. (1999). Inflammation:
Basic Principles and Clinical Correlates. Philadelphia: Lippincott Williams & Wilkins.
García-Bueno, B., Caso, J. R., & Leza, J. C. (2008). Stress as a neuroinflammatory condition
in brain: damaging and protective mechanisms. Neurosci Biobehav Rev 32,
1136–1151.
Gardoni, F., Boraso, M., Zianni, E., Corsini, E., Galli, C. L., Cattabeni, F., et al. (2011).
Distribution of interleukin-1 receptor complex at the synaptic membrane driven by
interleukin-1β and NMDA stimulation. J Neuroinflammation 8, 14.
Garey, L. (2010). When cortical development goes wrong: Schizophrenia as a
neurodevelopmental disease of microcircuits. J Anat 217, 324–333.
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, 1515–1520.
Gilmore, J. H., & Jarskog, L. F. (1997). Exposure to infection and brain development:
Cytokines in the pathogenesis of schizophrenia. Schizophr Res 24, 365–367.
Gogos, J. A., & Gerber, D. J. (2006). Schizophrenia susceptibility genes: Emergence of
positional candidates and future directions. Trends Pharmacol Sci 27, 226–233.
Gray, J. A., Feldon, J., Rawlins, J. N. P., Hemsley, D. R., & Smith, A. D. (1991). The
neuropsychology of schizophrenia. Behav Brain Sci 14, 1–84.
Günther, T., Konrad, K., De Brito, S. A., Herpertz-Dahlmann, B., & Vloet, T. D. (2011).
Attentional functions in children and adolescents with ADHD, depressive disorders,
and the comorbid condition. J Child Psychol Psychiatry 52, 324–331.
Haack, M., Hinze-Selch, D., Fenzel, T., Kraus, T., Kühn, M., Schuld, A., & Pollmächer, T.
(1999). Plasma levels of cytokines and soluble cytokine receptors in psychiatric
patients upon hospital admission: Effects of confounding factors and diagnosis. J
Psychiatr Res 33, 407–418.
Harrison, P. J., & Weinberger, D. R. (2005). Schizophrenia genes, gene expression, and
neuropathology: On the matter of their convergence. Mol Psychiatry 10, 40–68.
107
Harvey, P. D., Koren, D., Reichenberg, A., & Bowie, C. R. (2006). Negative symptoms and
cognitive deficits: What is the nature of their relationship? Schizophr Bull 32, 250–258.
Hayley, S., Wall, P., & Anisman, H. (2002). Sensitization to the neuroendocrine, central
monoamine and behavioural effects of murine tumor necrosis factor-alpha:
Peripheral and central mechanisms. Eur J Neurosci 15, 1061–1076.
He, G., Zhang, J., Li, X. W., Chen, W. Y., Pan, Y. X., Yang, F. P., et al. (2006). Interleukin-10–
1082 promoter polymorphism is associated with schizophrenia in a Han Chinese
sib-pair study. Neurosci Lett 394, 1–4.
Hilmas, C., Pereira, E. F., Alkondon, M., Rassoulpour, A., Schwarcz, R., & Albuquerque, E. X.
(2001). The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity
and increases non-alpha7 nicotinic receptor expression: Physiopathological implications. J Neurosci 21, 7463–7473.
Hinze-Selch, D., & Pollmächer, T. (2001). In vitro cytokine secretion in individuals with
schizophrenia: Results, confounding factors, and implications for further research.
Brain Behav Immun 15, 282–318.
Holden, J. M., Meyers-Manor, J. E., Overmier, J. B., Gahtan, E., Sweeney, W., & Miller, H.
(2008). Lipopolysaccharide-induced immune activation impairs attention but has
little effect on short-term working memory. Behav Brain Res 194, 138–145.
Hope, S., Melle, I., Aukrust, P., Steen, N. E., Birkenaes, A. B., Lorentzen, S., et al. (2009).
Similar immune profile in bipolar disorder and schizophrenia: Selective increase in
soluble tumor necrosis factor receptor I and von Willebrand factor. Bipolar Disord
11, 726–734.
Howes, O. D., & Kapur, S. (2009). The dopamine hypothesis of schizophrenia: Version III
—The final common pathway. Schizophr Bull 35, 549–562.
Huh, G. S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M., & Shatz, C. J. (2000).
Functional requirement for class I MHC in CNS development and plasticity. Science
290, 2155–2159.
Hulshoff Pol, H. E., & Kahn, R. S. (2008). What happens after the first episode? A review
of progressive brain changes in chronically ill patients with schizophrenia.
Schizophr Bull 34, 354–366.
Insel, T. R. (2010). Rethinking schizophrenia. Nature 468, 187–193.
Janeway, C. A., Jr., & Medzhitov, R. (2002). Innate immune recognition. Annu Rev
Immunol 20, 197–216.
Javitt, D. C. (2007). Glutamate and schizophrenia: Phencyclidine, N-methyl-D-aspartate
receptors, and dopamine-glutamate interactions. Int Rev Neurobiol 78, 69–108.
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, 38–42.
Kaiya, H., Uematsu, M., Ofuji, M., Nishida, A., Takeuchi, K., Nozaki, M., & Idaka, E. (1989).
Elevated plasma prostaglandin E2 levels in schizophrenia. J Neural Transm 77,
39–46.
Kapur, S. (2003). Psychosis as a state of aberrant salience: A framework linking biology,
phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160, 13–23.
Katila, H., Hänninen, K., & Hurme, M. (1999). Polymorphisms of the interleukin-1 gene
complex in schizophrenia. Mol Psychiatry 4, 179–181.
Kim, Y. K., Kim, L., & Lee, M. S. (2000). Relationships between interleukins, neurotransmitters and psychopathology in drug-free male schizophrenics. Schizophr Res 44,
165–175.
Kim, Y. K., Myint, A. M., Lee, B. H., Han, C. S., Lee, H. J., Kim, D. J., & Leonard, B. E. (2004).
Th1, Th2 and Th3 cytokine alteration in schizophrenia. Prog Neuropsychopharmacol
Biol Psychiatry 28, 1129–1134.
Kim, Y. K., Myint, A. M., Verkerk, R., Scharpe, S., Steinbusch, H., & Leonard, B. (2009).
Cytokine changes and tryptophan metabolites in medication-naïve and medication-free schizophrenic patients. Neuropsychobiology 59, 123–129.
Klosterkötter, J., Hellmich, M., Steinmeyer, E. M., & Schultze-Lutter, F. (2001). Diagnosing
schizophrenia in the initial prodromal phase. Arch Gen Psychiatry 58, 158–164.
Knüpfer, H., & Preiss, R. (2008). sIL-6R: More than an agonist? Immunol Cell Biol 86,
87–91.
Kumánovics, A., Takada, T., & Lindahl, K. F. (2003). Genomic organization of the
mammalian MHC. Annu Rev Immunol 21, 629–657.
Kunz, M., Ceresér, 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-α in patients with bipolar disorder and
schizophrenia: Differences in pro- and anti-inflammatory balance. Rev Bras
Psiquiatr (Epub ahead of print[PMID: 21412654]).
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 randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 71, 520–527.
Lahdelma, L., Ahokas, A., Andersson, L. C., Suvisaari, J., Hovatta, I., Huttunen, M. O., &
Koskimies, S. (2001). Human leukocyte antigen-A1 predicts a good therapeutic
response to clozapine with a low risk of agranulocytosis in patients with
schizophrenia. J Clin Psychopharmacol 21, 4–7.
Larson, S. J., & Dunn, A. J. (2001). Behavioral effects of cytokines. Brain Behav Immun 15,
371–387.
Larson, M. K., Walker, E. F., & Compton, M. T. (2010). Early signs, diagnosis and
therapeutics of the prodromal phase of schizophrenia and related psychotic
disorders. Expert Rev Neurother 10, 1347–1359.
Lavoie, S., Murray, M. M., Deppen, P., Knyazeva, M. G., Berk, M., Boulat, O., et al. (2008).
Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in
schizophrenia patients. Neuropsychopharmacology 33, 2187–2199.
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,
138–149.
Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005). Cortical inhibitory neurons and
schizophrenia. Nat Rev Neurosci 6, 312–324.
Lewis, D. A., & Moghaddam, B. (2006). Cognitive dysfunction in schizophrenia: Convergence
of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63, 1372–1376.
108
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
Licinio, J., Seibyl, J. P., Altemus, M., Charney, D. S., & Krystal, J. H. (1993). Elevated CSF levels of
interleukin-2 in neuroleptic-free schizophrenic patients. Am J Psychiatry 150, 1408–1410.
Lin, A., Kenis, G., Bignotti, S., Tura, G. J., De Jong, R., Bosmans, E., et al. (1998). The
inflammatory response system in treatment-resistant schizophrenia: increased
serum interleukin-6. Schizophr Res 32, 9–15.
Linderholm, K. R., Skogh, E., Olsson, S. K., Dahl, M. L., Holtze, M., Engberg, G., et al. (in
press). Increased levels of kynurenine and kynurenic acid in the CSF of patients
with schizophrenia. Schizophr Bullin, (Epub ahead of print [PMID: 20729465]).
Liu, L., Jia, F., Yuan, G., Chen, Z., Yao, J., Li, H., & Fang, C. (2010). Tyrosine hydroxylase,
interleukin-1beta and tumor necrosis factor-alpha are overexpressed in peripheral
blood mononuclear cells from schizophrenia patients as determined by semiquantitative analysis. Psychiatry Res 176, 1–7.
Lynch, M. A. (2004). Long-term potentiation and memory. Physiol Rev 84, 87–136.
Maes, M., Bocchio Chiavetto, L., Bignotti, S., Battisa, Tura, G. J., Pioli, R., et al. (2002).
Increased serum interleukin-8 and interleukin-10 in schizophrenic patients
resistant to treatment with neuroleptics and the stimulatory effects of clozapine
on serum leukemia inhibitory factor receptor. Schizophr Res 54, 281–291.
Maes, M., Bosmans, E., Kenis, G., De Jong, R., Smith, R. S., & Meltzer, H. Y. (1997). In vivo
immunomodulatory effects of clozapine in schizophrenia. Schizophr Res 26, 221–225.
Maes, M., Bosmans, E., Ranjan, R., Vandoolaeghe, E., Meltzer, H. Y., De Ley, M., et al.
(1996). Lower plasma CC16, a natural anti-inflammatory protein, and increased
plasma interleukin-1 receptor antagonist in schizophrenia: effects of antipsychotic
drugs. Schizophr Res 21, 39–50.
Maes, M., Meltzer, H. Y., & Bosmans, E. (1994). Immune-inflammatory markers in
schizophrenia: Comparison to normal controls and effects of clozapine. Acta
Psychiatr Scand 89, 346–351.
Marder, S. R., Essock, S. M., Miller, A. L., Buchanan, R. W., Casey, D. E., Davis, J. M., et al.
(2004). Physical health monitoring of patients with schizophrenia. Am J Psychiatry
161, 1334–1349.
Marsland, A. L., Petersen, K. L., Sathanoori, R., Muldoon, M. F., Neumann, S. A., Ryan, C.,
et al. (2006). Interleukin-6 covaries inversely with cognitive performance among
middle-aged community volunteers. Psychosom Med 68, 895–903.
Martin, L. F., & Freedman, R. (2007). Schizophrenia and the alpha7 nicotinic
acetylcholine receptor. Int Rev Neurobiol 78, 225–246.
Mata, I., Crespo-Facorro, B., Pérez-Iglesias, R., Carrasco-Marín, E., Arranz, M. J., PelayoTerán, J. M., et al. (2006). Association between the interleukin-1 receptor
antagonist gene and negative symptom improvement during antipsychotic
treatment. Am J Med Genet B Neuropsychiatr Genet 141B, 939–943.
McAfoose, J., & Baune, B. T. (2009). Evidence for a cytokine model of cognitive function.
Neurosci Biobehav Rev 33, 355–366.
McAllister, C. G., van Kammen, D. P., Rehn, T. J., Miller, A. L., Gurklis, J., Kelley, M. E., et al.
(1995). Increases in CSF levels of interleukin-2 in schizophrenia: Effects of
recurrence of psychosis and medication status. Am J Psychiatry 152, 1291–1297.
McGauley, G. A., Aldridge, C. R., Fahy, T. A., & Eastment, C. (1989). The dexamethasone
suppression test and negative symptoms of schizophrenia. Acta Psychiatr Scand 80,
548–553.
McGlashan, T. H. (1996). Early detection and intervention in schizophrenia: research.
Schizophr Bull 22, 327–345.
McGlashan, T. H., Zipursky, R. B., Perkins, D., Addington, J., Miller, T. J., Woods, S. W.,
et al. (2003). The PRIME North America randomized double-blind clinical trial of
olanzapine versus placebo in patients at risk of being prodromally symptomatic for
psychosis. I. Study rationale and design. Schizophr Res 61, 7–18.
McGlashan, T. H., Zipursky, R. B., Perkins, D., Addington, J., Miller, T., Woods, S. W., et al.
(2006). Randomized, double-blind trial of olanzapine versus placebo in patients
prodromally symptomatic for psychosis. Am J Psychiatry 163, 790–799.
Merlot, E., Couret, D., & Otten, W. (2008). Prenatal stress, fetal imprinting and
immunity. Brain Behav Immun 22, 42–51.
Meyer, U., Engler, A., Weber, L., Schedlowski, M., & Feldon, J. (2008). Preliminary
evidence for a modulation of fetal dopaminergic development by maternal immune
activation during pregnancy. Neuroscience 154, 701–709.
Meyer, U., & Feldon, J. (2010). Epidemiology-driven neurodevelopmental animal
models of schizophrenia. Prog Neurobiol 90, 285–326.
Meyer, U., Feldon, J., & Yee, B. K. (2009). A review of the fetal brain cytokine imbalance
hypothesis of schizophrenia. Schizophr Bull 35, 959–972.
Meyer, U., Murray, P. J., Urwyler, A., Yee, B. K., Schedlowski, M., & Feldon, J. (2008). Adult
behavioral and pharmacological dysfunctions following disruption of the fetal
brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory
signaling. Mol Psychiatry 13, 208–221.
Meyer, U., Feldon, J., & Dammann, O. (2011). Schizophrenia and autism: both shared
and disorder-specific pathogenesis via perinatal inflammation? Pediatr Res 69,
26R–33R.
Miyaoka, T., Yasukawa, R., Yasuda, H., Hayashida, M., Inagaki, T., & Horiguchi, J. (2008).
Minocycline as adjunctive therapy for schizophrenia: an open-label study. Clin
Neuropharmacol 31, 287–292.
Mogensen, T. H. (2009). Pathogen recognition and inflammatory signaling in innate
immune defenses. Clin Microbiol Rev 22, 240–273.
Möller, H. J. (2007). Clinical evaluation of negative symptoms in schizophrenia. Eur
Psychiatry 22, 380–386.
Monji, A., Kato, T., & Kanba, S. (2009). Cytokines and schizophrenia: Microglia
hypothesis of schizophrenia. Psychiatry Clin Neurosci 63, 257–265.
Morgan, C. J., Mofeez, A., Brandner, B., Bromley, L., & Curran, H. V. (2004). Acute effects
of ketamine on memory systems and psychotic symptoms in healthy volunteers.
Neuropsychopharmacology 29, 208–218.
Müller, N. (2008). Inflammation and the glutamate system in schizophrenia:
Implications for therapeutic targets and drug development. Expert Opin Ther
Targets 12, 1497–1507.
Müller, N., & Ackenheil, M. (1995). Immunoglobulin and albumin content of
cerebrospinal fluid in schizophrenic patients: Relationship to negative symptomatology. Schizophr Res 14, 223–228.
Müller, N., Ackenheil, M., Hofschuster, E., Mempel, W., & Eckstein, R. (1991). Cellular
immunity in schizophrenic patients before and during neuroleptic treatment.
Psychiatry Res 37, 147–160.
Müller, N., Dobmeier, P., Empl, M., Riedel, M., Schwarz, M., & Ackenheil, M. (1997b).
Soluble IL-6 receptors in the serum and cerebrospinal fluid of paranoid
schizophrenic patients. Eur Psychiatry 12, 294–299.
Müller, N., Empl, M., Riedel, M., Schwarz, M., & Ackenheil, M. (1997b). Neuroleptic
treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in
schizophrenia. Eur Arch Psychiatry Clin Neurosci 247, 308–313.
Müller, 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, 118–124.
Müller, N., Myint, A. M., & Schwarz, M. J. (2009). The impact of neuroimmune
dysregulation on neuroprotection and neurotoxicity in psychiatric disorders—
Relation to drug treatment. Dialogues Clin Neurosci 11, 319–332.
Müller, N., Riedel, M., Gruber, R., Ackenheil, M., & Schwarz, M. J. (2000). The
immune system and schizophrenia. An integrative view. Ann N Y Acad Sci 917,
456–467.
Müller, N., Riedel, M., Scheppach, C., Brandstätter, B., Sokullu, S., Krampe, K., et al.
(2002). Beneficial antipsychotic effects of celecoxib add-on therapy compared to
risperidone alone in schizophrenia. Am J Psychiatry 159, 1029–1034.
Müller, N., Riedel, M., Schwarz, M. J., & Engel, R. R. (2005). Clinical effects of COX-2
inhibitors on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci 255,
149–151.
Müller, N., & Schwarz, M. J. (2007). The immune-mediated alteration of serotonin
and glutamate: Towards an integrated view of depression. Mol Psychiatry 12,
988–1000.
Müller, N., & Schwarz, M. J. (2008). COX-2 inhibition in schizophrenia and major
depression. Curr Pharm Des 14, 1452–1465.
Müller, N., & Schwarz, M. J. (2010). Immune system and schizophrenia. Curr Immunol
Rev 6, 213–220.
Murray, P. J. (2006). Understanding and exploiting the endogenous interleukin-10/
STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol 6, 379–386.
Na, K. S., & Kim, Y. K. (2007). Monocytic, Th1 and th2 cytokine alterations in the
pathophysiology of schizophrenia. Neuropsychobiology 56, 55–63.
Naudin, J., Capo, C., Giusano, B., Mège, J. L., & Azorin, J. M. (1997). A differential role for
interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res 26,
227–233.
Neill, J. C., Barnes, S., Cook, S., Grayson, B., Idris, N. F., McLean, S. L., et al. (2010). Animal
models of cognitive dysfunction and negative symptoms of schizophrenia: Focus
on NMDA receptor antagonism. Pharmacol Ther 128, 419–432.
Nelson, B. H., & Willerford, D. M. (1998). Biology of the interleukin-2 receptor. Adv
Immunol 70, 1–81.
Nieratschker, V., Frank, J., Mühleisen, T. W., Strohmaier, J., Wendland, J. R., Schumacher,
J., et al. (2010). The catechol-O-methyl transferase (COMT) gene and its potential
association with schizophrenia: Findings from a large German case-control and
family-based sample. Schizophr Res 122, 24–30.
Nilsson, L. K., Linderholm, K. R., Engberg, G., Paulson, L., Blennow, K., Lindström, L. H.,
et al. (2005). Elevated levels of kynurenic acid in the cerebrospinal fluid of male
patients with schizophrenia. Schizophr Res 80, 315–322.
O'Donnell, M. C., Catts, S. V., Ward, P. B., Liebert, B., Lloyd, A., Wakefield, D., &
McConaghy, N. (1996). Increased production of interleukin-2 (IL-2) but not soluble
interleukin-2 receptors (sIL-2R) in unmedicated patients with schizophrenia and
schizophreniform disorder. Psychiatry Res 65, 171–178.
O'Donovan, M. C., Craddock, N. J., & Owen, M. J. (2009). Genetics of psychosis; insights
from views across the genome. Hum Genet 126, 3–12.
Papiol, S., Molina, V., Desco, M., Rosa, A., Reig, S., Gispert, J. D., et al. (2005). Ventricular
enlargement in schizophrenia is associated with a genetic polymorphism at the
interleukin-1 receptor antagonist gene. Neuroimage 27, 1002–1006.
Paul-Samojedny, M., Kowalczyk, M., Suchanek, R., Owczarek, A., Fila-Danilow, A.,
Szczygiel, A., & Kowalski, J. (2010). Functional polymorphism in the interleukin-6
and interleukin-10 genes in patients with paranoid schizophrenia—A case-control
study. J Mol Neurosci 42, 112–119.
Pedersen, A., Diedrich, M., Kaestner, F., Koelkebeck, K., Ohrmann, P., Ponath, G., et al.
(2008). Memory impairment correlates with increased S100B serum concentrations
in patients with chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32,
1789–1792.
Perkins, D. O., Gu, H., Boteva, K., & Lieberman, J. A. (2005). Relationship between
duration of untreated psychosis and outcome in first-episode schizophrenia: A
critical review and meta-analysis. Am J Psychiatry 162, 1785–1804.
Phillips, L. J., McGorry, P. D., Garner, B., Thompson, K. N., Pantelis, C., Wood, S. J., & Berger, G.
(2006). Stress, the hippocampus and the hypothalamic–pituitary–adrenal axis:
Implications for the development of psychotic disorders. Aust N Z J Psychiatry 40,
725–741.
Pollmächer, T., Haack, M., Schuld, A., Kraus, T., & Hinze-Selch, D. (2000). Effects of
antipsychotic drugs on cytokine networks. J Psychiatr Res 34, 369–382.
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, 801–808.
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. Nature 460, 748–752.
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
Radewicz, K., Garey, L. J., Gentleman, S. M., & Reynolds, R. (2000). Increase in HLA-DR
immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neurol 59, 137–150.
Raison, C. L., & Miller, A. H. (2003). When not enough is too much: The role of
insufficient glucocorticoid signaling in the pathophysiology of stress-related
disorders. Am J Psychiatry 160, 1554–1565.
Ransohoff, R. M., & Perry, V. H. (2009). Microglial physiology: Unique stimuli,
specialized responses. Annu Rev Immunol 27, 119–145.
Rapaport, M. H., Delrahim, K. K., Bresee, C. J., Maddux, R. E., Ahmadpour, O., & Dolnak, D.
(2005). Celecoxib augmentation of continuously ill patients with schizophrenia.
Biol Psychiatry 57, 1594–1596.
Rapaport, M. H., McAllister, C. G., Pickar, D., Tamarkin, L., Kirch, D. G., & Paul, S. M.
(1997). CSF IL-1 and IL-2 in medicated schizophrenic patients and normal
volunteers. Schizophr Res 25, 123–129.
Reale, M., Patruno, A., De Lutiis, M. A., Pesce, M., Felaco, M., Di Giannantonio, M., et al.
(2011). Dysregulation of chemo-cytokine production in schizophrenic patients
versus healthy controls. BMC Neurosci 12, 13.
Reichenberg, A. (2005). Cognitive impairment as a risk factor for psychosis. Dialogues
Clin Neurosci 7, 31–38.
Rhen, T., & Cidlowski, J. A. (2005). Antiinflammatory action of glucocorticoids—New
mechanisms for old drugs. N Engl J Med 353, 1711–1723.
Rivest, S. (2010). Interactions between the immune and neuroendocrine systems. Prog
Brain Res 181, 43–53.
Romero, E., Guaza, C., Castellano, B., & Borrell, J. (2010). Ontogeny of sensorimotor
gating and immune impairment induced by prenatal immune challenge in rats:
Implications for the etiopathology of schizophrenia. Mol Psychiatry 15, 372–383.
Rothermundt, M., Ahn, J. N., & Jörgens, S. (2009). S100B in schizophrenia: An update.
Gen Physiol Biophys 28, F76–F81.
Rothermundt, M., Arolt, V., Weitzsch, C., Eckhoff, D., & Kirchner, H. (1998).
Immunological dysfunction in schizophrenia: A systematic approach. Neuropsychobiology 37, 186–193.
Rothermundt, M., Ponath, G., Glaser, T., Hetzel, G., & Arolt, V. (2004). S100B serum
levels and long-term improvement of negative symptoms in patients with
schizophrenia. Neuropsychopharmacology 29, 1004–1011.
Samuelsson, A. M., Jennische, E., Hansson, H. A., & Holmäng, A. (2006). Prenatal
exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning. Am J
Physiol Regul Integr Comp Physiol 290, R1345–R1356.
Sanders, A. R., Duan, J., Levinson, D. F., Shi, J., He, D., Hou, C., et al. (2008). No significant
association of 14 candidate genes with schizophrenia in a large European ancestry
sample: Implications for psychiatric genetics. Am J Psychiatry 165, 497–506.
Sathyasaikumar, K. V., Stachowski, E. K., Wonodi, I., Roberts, R. C., Rassoulpour, A.,
McMahon, R. P., & Schwarcz, R. (in press). Impaired kynurenine pathway
metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr
Bull, (Epub ahead of print [PMID: 21036897]).
Saviouk, V., Chow, E. W., Bassett, A. S., & Brzustowicz, L. M. (2005). Tumor necrosis
factor promoter haplotype associated with schizophrenia reveals a linked locus on
1q44. Mol Psychiatry 10, 375–383.
Schmitt, A., Leonardi-Essmann, F., Durrenberger, P. F., Parlapani, E., Schneider-Axmann,
T., Spanagel, R., et al. (2011). Regulation of immune-modulatory genes in left
superior temporal cortex of schizophrenia patients: a genome-wide microarray
study. World J Biol Psychiatry 12, 201–215.
Schneider, H., Pitossi, F., Balschun, D., Wagner, A., del Rey, A., & Besedovsky, H. O.
(1998). A neuromodulatory role of interleukin-1beta in the hippocampus. Proc Natl
Acad Sci USA 95, 7778–7783.
Schwab, S. G., Mondabon, S., Knapp, M., Albus, M., Hallmayer, J., Borrmann-Hassenbach,
M., et al. (2003). Association of tumor necrosis factor alpha gene-G308A
polymorphism with schizophrenia. Schizophr Res 65, 19–25.
Segrin, C. (2000). Social skills deficits associated with depression. Clin Psychol Rev 20,
379–403.
Serhan, C. N., & Savill, J. (2005). Resolution of inflammation: The beginning programs
the end. Nat Immunol 6, 1191–1197.
Seth, P., & Koul, N. (2008). Astrocyte, the star avatar: Redefined. J Biosci 33, 405–421.
Shatz, C. J. (2009). MHC class I: An unexpected role in neuronal plasticity. Neuron 64,
40–45.
Shi, J., Levinson, D. F., Duan, J., Sanders, A. R., Zheng, Y., Pe'er, I., et al. (2009). Common
variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460,
753–757.
Silver, H. (2004). Selective serotonin re-uptake inhibitor augmentation in the treatment of
negative symptoms of schizophrenia. Expert Opin Pharmacother 5, 2053–2058.
Sirota, P., Meiman, M., Herschko, R., & Bessler, H. (2005). Effect of neuroleptic
administration on serum levels of soluble IL-2 receptor-alpha and IL-1 receptor
antagonist in schizophrenic patients. Psychiatry Res 134, 151–159.
Smith, R. S. (1991). The immune system is a key factor in the etiology of psychosocial
disease. Med Hypotheses 34, 49–57.
Smith, S. E., Li, J., Garbett, K., Mirnics, K., & Patterson, P. H. (2007). Maternal immune
activation alters fetal brain development through interleukin-6. J Neurosci 27,
10695–10702.
Söderlund, J., Schröder, J., Nordin, C., Samuelsson, M., Walther-Jallow, L., Karlsson, H.,
et al. (2009). Activation of brain interleukin-1beta in schizophrenia. Mol Psychiatry
14, 1069–1071.
Song, C., Lin, A., Kenis, G., Bosmans, E., & Maes, M. (2000). Immunosuppressive effects of
clozapine and haloperidol: Enhanced production of the interleukin-1 receptor
antagonist. Schizophr Res 42, 157–164.
Song, X. Q., Lv, L. X., Li, W. Q., Hao, Y. H., & Zhao, J. P. (2009). The interaction of nuclear factorkappa B and cytokines is associated with schizophrenia. Biol Psychiatry 65, 481–488.
109
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,
744–747.
Steiner, J., Bielau, H., Brisch, R., Danos, P., Ullrich, O., Mawrin, C., et al. (2008).
Immunological aspects in the neurobiology of suicide: Elevated microglial density
in schizophrenia and depression is associated with suicide. J Psychiatr Res 42,
151–157.
Steiner, J., Mawrin, C., Ziegeler, A., Bielau, H., Ullrich, O., Bernstein, H. G., & Bogerts, B.
(2006). Distribution of HLA-DR-positive microglia in schizophrenia reflects
impaired cerebral lateralization. Acta Neuropathol 112, 305–316.
Sugino, H., Futamura, T., Mitsumoto, Y., Maeda, K., & Marunaka, Y. (2009). Atypical
antipsychotics suppress production of proinflammatory cytokines and up-regulate
interleukin-10 in lipopolysaccharide-treated mice. Prog Neuropsychopharmacol Biol
Psychiatry 33, 303–307.
Sullivan, P. F. (2005). The genetics of schizophrenia. PLoS Med 2, e212.
Sun, S., Wang, F., Wei, J., Cao, L. Y., Qi, L. Y., Xiu, M. H., et al. (2008). Association between
interleukin-6 receptor polymorphism and patients with schizophrenia. Schizophr
Res 102, 346–347.
Tandon, R., Keshavan, M. S., & Nasrallah, H. A. (2008). Schizophrenia, “just the facts”
what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 102, 1–18.
Tandon, R., Nasrallah, H. A., & Keshavan, M. S. (2009). Schizophrenia, “just the facts” 4.
Clinical features and conceptualization. Schizophr Res 110, 1–23.
Tandon, R., Nasrallah, H. A., & Keshavan, M. S. (2010). Schizophrenia, “just the facts” 5.
Treatment and prevention. Past, present, and future. Schizophr Res 122, 1–23.
Theodoropoulou, S., Spanakos, G., Baxevanis, C. N., Economou, M., Gritzapis, A. D.,
Papamichail, M. P., & Stefanis, C. N. (2001). Cytokine serum levels, autologous
mixed lymphocyte reaction and surface marker analysis in never medicated and
chronically medicated schizophrenic patients. Schizophr Res 47, 13–25.
Toyooka, K., Watanabe, Y., Iritani, S., Shimizu, E., Iyo, M., Nakamura, R., et al. (2003). A
decrease in interleukin-1 receptor antagonist expression in the prefrontal cortex of
schizophrenic patients. Neurosci Res 46, 299–307.
van Berckel, B. N., Bossong, M. G., Boellaard, R., Kloet, R., Schuitemaker, A., Caspers, E.,
et al. (2008). Microglia activation in recent-onset schizophrenia: A quantitative
(R)-[11 C]PK11195 positron emission tomography study. Biol Psychiatry 64,
820–822.
van Kammen, D. P., McAllister-Sistilli, C. G., Kelley, M. E., Gurklis, J. A., & Yao, J. K. (1999).
Elevated interleukin-6 in schizophrenia. Psychiatry Res 87, 129–136.
van Os, J., & Kapur, S. (2009). Schizophrenia. Lancet 374, 635–645.
Vawter, M. P., Dillon-Carter, O., Issa, F., Wyatt, R. J., & Freed, W. J. (1997). Transforming
growth factors beta 1 and beta 2 in the cerebrospinal fluid of chronic schizophrenic
patients. Neuropsychopharmacology 16, 83–87.
Vuillermot, S., Weber, L., Feldon, J., & Meyer, U. (2010). A longitudinal examination of
the neurodevelopmental impact of prenatal immune activation in mice reveals
primary defects in dopaminergic development relevant to schizophrenia. J Neurosci
30, 1270–1287.
Wang, J. (2010). Preclinical and clinical research on inflammation after intracerebral
hemorrhage. Prog Neurobiol 92, 463–477.
Weinberger, D. R. (1987). Implications of normal brain development for the
pathogenesis of schizophrenia. Arch Gen Psychiatry 44, 660–669.
Wonodi, I., & Schwarcz, R. (2010). Cortical kynurenine pathway metabolism: A
novel target for cognitive enhancement in schizophrenia. Schizophr Bull 36,
211–218.
Wood, S. J., Pantelis, C., Velakoulis, D., Yücel, M., Fornito, A., & McGorry, P. D. (2008).
Progressive changes in the development toward schizophrenia: Studies in subjects
at increased symptomatic risk. Schizophr Bull 34, 322–329.
Woods, S. W., Breier, A., Zipursky, R. B., Perkins, D. O., Addington, J., Miller, T. J., et al.
(2003). Randomized trial of olanzapine versus placebo in the symptomatic acute
treatment of the schizophrenic prodrome. Biol Psychiatry 54, 453–464.
Xu, M., & He, L. (2010). Convergent evidence shows a positive association of
interleukin-1 gene complex locus with susceptibility to schizophrenia in the
Caucasian population. Schizophr Res 120, 131–142.
Yamamoto, K., & Hornykiewicz, O. (2004). Proposal for a noradrenaline hypothesis of
schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28, 913–922.
Yang, C. R., & Svensson, K. A. (2008). Allosteric modulation of NMDA receptor via
elevation of brain glycine and D-serine: The therapeutic potentials for schizophrenia. Pharmacol Ther 120, 317–332.
Yeragani, V. K. (1990). The incidence of abnormal dexamethasone suppression in
schizophrenia: A review and a meta-analytic comparison with the incidence in
normal controls. Can J Psychiatry 35, 128–132.
Yoshimura, A., Wakabayashi, Y., & Mori, T. (2010). Cellular and molecular basis for the
regulation of inflammation by TGF-beta. J Biochem 147, 781–792.
Yu, L., Yang, M. S., Zhao, J., Shi, Y. Y., Zhao, X. Z., Yang, J. D., et al. (2004). An association
between polymorphisms of the interleukin-10 gene promoter and schizophrenia in
the Chinese population. Schizophr Res 71, 179–183.
Yung, A. R., & McGorry, P. D. (1996). The initial prodrome in psychosis: Descriptive and
qualitative aspects. Aust N Z J Psychiatry 30, 587–599.
Zai, G., Müller, D. J., Volavka, J., Czobor, P., Lieberman, J. A., Meltzer, H. Y., & Kennedy, J. L.
(2006). Family and case-control association study of the tumor necrosis factoralpha (TNF-alpha) gene with schizophrenia and response to antipsychotic
medication. Psychopharmacology 188, 171–182.
Zalcman, S., Green-Johnson, J. M., Murray, L., Nance, D. M., Dyck, D., Anisman, H., &
Greenberg, A. H. (1994). Cytokine-specific central monoamine alterations induced
by interleukin-1, -2 and -6. Brain Res 643, 40–49.
Zanardini, R., Bocchio-Chiavetto, L., Scassellati, C., Bonvicini, C., Tura, G. B., Rossi, G., et al.
(2003). Association between IL-1beta -511 C/T and IL-1RA (86 bp)n repeats
polymorphisms and schizophrenia. J Psychiatr Res 37, 457–462.
110
U. Meyer et al. / Pharmacology & Therapeutics 132 (2011) 96–110
Zhang, L., Liu, W., Alizadeh, D., Zhao, D., Farrukh, O., Lin, J., et al. (2011). S100B
attenuates microglia activation in gliomas: Possible role of STAT3 pathway. Glia 59,
486–498.
Zhang, X. Y., Zhou, D. F., Cao, L. Y., Wu, G. Y., & Shen, Y. C. (2005). Cortisol and cytokines in
chronic and treatment-resistant patients with schizophrenia: Association with
psychopathology and response to antipsychotics. Neuropsychopharmacology 30,
1532–1538.
Zhang, X. Y., Zhou, D. F., Qi, L. Y., Chen, S., Cao, L. Y., Chen da, C., et al. (2009). Superoxide
dismutase and cytokines in chronic patients with schizophrenia: Association with
psychopathology and response to antipsychotics. Psychopharmacology 204,
177–184.
Zhang, X. Y., Zhou, D. F., Zhang, P. Y., Wu, G. Y., Cao, L. Y., & Shen, Y. C. (2002). Elevated
interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free
schizophrenia: Association with psychopathology. Schizophr Res 57, 247–258.
Zorrilla, E. P., Cannon, T. D., Gur, R. E., & Kessler, J. (1996). Leukocytes and organnonspecific autoantibodies in schizophrenics and their siblings: Markers of
vulnerability or disease? Biol Psychiatry 40, 825–833.