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REVIEW ARTICLE
Objective Research into psychoneuroimmunology has led to substantial advances in our understanding of the reciprocal interactions
between the central nervous system and the immune system in neuropsychiatric disorders. To date, the presence of inammatory responses
and the crucial role of cytokines in major depression have been addressed in numerous studies. However, neuroinammatory hypotheses in
anxiety disorders have been studied less extensively than in major depression. There is a high research need for better understanding of both
the heterogeneous role of specic cytokines in the control of anxious states and in different anxiety disorders and of the immunomodulating
effects of antidepressants on anxiety.
Methods Relevant literature was identied through a search of MEDLINE via PubMed. We discuss recent research on neuroimmunology
in anxiety and make methodological recommendations for future investigation of neuroinammatory hypotheses in anxiety disorders.
Results Some accumulating evidence has indicated modulatory effects of cytokines on neuronal communication and anxiety; however,
research has not revealed consistent reproducible ndings.
Conclusions The availability of inammatory biomarkers may provide an opportunity to identify patients via specic pathophysiological
processes and to monitor therapeutic responses within relevant pathways. Further understanding of the neuroimmunological mechanisms to
untangle the reciprocal associations between inammation and anxiety is warranted. Copyright 2011 John Wiley & Sons, Ltd.
key wordsneuroimmunology; anxiety disorders; cytokines
INTRODUCTION
METHODS
Over the past 30 years, research into psychoneuroimmunology, the study of neural-endocrine-immune system interactions, has led to substantial advances in our
understanding of the reciprocal interactions between
the central nervous system (CNS) and the immune
system in neuropsychiatric disorders (Ader et al.,
1995; Raison et al., 2006; Leonard and Myint, 2009;
Miller et al., 2009). Experimental and clinical research
reveals the pivotal roles of cytokines signalling the
brain to produce neurochemical, neuroendocrine, neuroimmune and behavioural changes (Kronfol and
Remick, 2000; Maier, 2003; Dantzer et al., 2008b;
Loftis et al., 2010; Capuron and Miller, 2011). Greater
understanding of the role of cytokines in the bidirectional communications between the nervous and
immune systems has inspired integrative, explanatory
models for neuropsychiatric disorders.
paper. We also hand-searched the reference list of relevant studies and reviews to aid identication of further
studies. We identied 584 references and 103 were
included in this review.
CYTOKINES AND
PSYCHONEUROIMMUNOLOGY
Just as the nervous and endocrine systems convey
information to the immune system via neurotransmitters and hormones, the immune system conveys
information to the nervous and endocrine systems via
cytokines and chemokines (Leonard and Myint,
2009). Cytokines are soluble bioactive mediators
released by various cell types both at the periphery
(such as monocytes and macrophages) and in the brain
(such as microglia, astrocytes, oligodendroglia and
neurons), which operate within a complex network
and act either synergistically or antagonistically. They
are generally associated with inammation, immune
activation and cell differentiation or death and include
interleukins (ILs), tumour necrosis factors (TNFs),
interferons (IFNs), chemokines and growth factors
(such as brain-derived neurotrophic factor) (Allan and
Rothwell, 2003). Based on the functional prole of
an immune response, cytokine production is orchestrated by type 1 helper cells (Th1) that generally mediate a pro-inammatory cellular immune response, and
type 2 helper cells (Th2) that enhance humoral
immune reactions. Pro-inammatory cytokines, such
as IL-1, IL-6, INF-g and TNFa, enhance the immune
response to help speed the elimination of pathogens
and the resolution of the inammatory challenge;
anti-inammatory cytokines, such as IL-4, IL-10 and
IL-13, serve to dampen the immune response via
decreasing cell function and synthesis of proinammatory cytokines (Kronfol and Remick, 2000).
The balance between Th1 and Th2 is an essential
determinant in containing the inammatory response
(Dantzer et al., 2008a), and a delicate balance of
pro-inammatory and anti-inammatory cytokines is
required for normal regulation of neuropsychiatric
functioning (Loftis et al., 2010). In addition to the
Th1 and Th2 cytokines, there is evidence that T helper
type 3 cells exert their action primarily by secreting
transforming growth factor beta-1 that facilitates a
balance between the Th1 and Th2 arms of cellular
immunity(Myint et al., 2005).
Cytokines have been implicated in the modulation of
neuronal activity in regions such as the amygdala,
hippocampus, hypothalamus and cerebral cortex
(Besedovsky and del Rey, 1996; Elenkov et al.,
2000). Peripheral cytokine signals can reach the brain
Copyright 2011 John Wiley & Sons, Ltd.
sample exploring also gender differences. When normal volunteers were injected with lipopolysaccharide,
a well-known immune activator, they exhibited acute
increases in symptoms of anxiety (Reichenberg et al.,
2001). When compared with non-anxious participants,
clinically anxious participants exhibited signicantly
higher levels of IL-6, independent of depressive symptoms that indicate an anxiety-specic effect on inammatory activity and highlights a pathway by which
anxiety may increase risk for inammatory diseases
(ODonovan et al., 2010).
Inammatory responses in anxiety disorders
Studies in clinical populations have shown that a high
level of anxiety is associated with impaired cellular
immunity. Anxiety disorders of special immunological
interest are PTSD, PD, OCD and GAD.
Post-traumatic stress disorder. Anxiety is associated
with increased circulating levels of CRP, IL-6,
TNF-a, IL-1b and IL-8 in patients with PTSD, which
may be due to an insufcient regulation of immune
function (Rohleder et al., 2004; Gill et al., 2008; Gill
et al., 2009; von Kanel et al., 2010; Pace and Heim,
2011). The strong evidence for systemic inammation and deleterious health consequences in PTSD
has been most well-documented disorders, and a
recent review has suggested that cellular immunity
is implicated in PTSD risk and resilience (Baker
et al., 2011).
Panic disorder. Alterations in circulating levels of
IL-1 have previously been demonstrated in patients
with PD (Brambilla et al., 1994). Reduced anxiety level
by therapeutic interventions (cognitive behavioural therapy and the anxiolytic ethyl loazepate) has been found
to be associated with decreased cell-mediated immunity
(Koh and Lee, 2004). A prospective experimentally
induced stress study demonstrates that 35% CO2 inhalation induced signicantly higher levels of anxiety in PD
patients as compared with the control subjects, but no
differences in immune parameters were found, either in
basal conditions or after experimental panic induction
(van Duinen et al., 2008).
Obsessive-compulsive disorder. Immunological ndings from OCD studies are equivocal. Whereas several
reports found no IL-6 differences in OCD, either in
plasma or in cerebrospinal uid (CSF) (Monteleone
et al., 1998; Carpenter et al., 2002), a decrease in production of TNF-a and the low levels of lipopolysaccharide-stimulated IL-6 have been reported (Denys
et al., 2004; Fluitman et al., 2010), which is in contrast
Hum. Psychopharmacol Clin Exp 2012; 27: 614.
DOI: 10.1002/hup
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is required for normal regulation of neuropsychiatric functioning (Loftis et al., 2010). It would be
useful to test the pattern of immune dysregulation, such as whether an anxious state is characterized by a shift in the pro/anti-inammatory or Th1/
Th2 cytokine ratio.
(3) Standardized behavioural assessments and record
of inammatory events
Clinical tools for assessing anxious state and
recording inammatory events should be standardized and made available for clinical research.
Appropriate monitoring techniques should be developed for assessing short-term uctuations in clinical
symptoms.
(4) Vulnerability factors
A variety of vulnerability factors and demographic
characteristics may potentially affect the direction
and magnitude of cytokine changes in response to
stress/anxious state including:
(a) Body mass index (BMI): BMI has been shown to
correlate with increased peripheral markers of
inammation, in part related to the capacity of
adipose tissue to produce IL-6 and other cytokines
(Vgontzas et al., 2000; Kern et al., 2001). Obesity
is associated with low-grade inammatory processes, with increased circulating levels of
acute phase proteins (CRP in particular) and
pro-inammatory cytokines.
(b) Ageing: Epidemiological studies indicate that anxiety disorders are more common among older age
individuals (Wolitzky-Taylor et al., 2010). Normal
ageing is characterized by chronic low-grade
inammatory factors, with an over-expression of
periphery pro-inammatory cytokines and impaired
pro-inammatory versus anti-inammatory balance
(Capuron and Miller, 2011).
(c) Medical conditions: The presence of medical
conditions, in particular, the presence of acute or
chronic inammatory challenge.
(d) Childhood history: Adverse childhood experiences
have been described as major environmental risk
factors and the extent of prior stress exposure
should be considered.
(e) Exercise: Skeletal muscle has now been viewed as
an immunogenic organ that by contraction stimulates the production of cytokines, such as IL-6.
Exercise affects circulating cytokine levels, and
this impact has been a remarkably consistent
research nding (Suzuki et al., 2002; Woods et al.,
2006; Pedersen and Febbraio, 2008).
Copyright 2011 John Wiley & Sons, Ltd.
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