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Charles L. Raison, Monica Kelly Cowles, Andrew H. Miller: Chapter 9. Brain–Immune System Interactions: Relevance to
the Pathophysiology and Treatment of Neuropsychiatric Disorders, in The American Psychiatric Publishing Textbook of
Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American
Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.417357. Printed 5/10/2009 from
www.psychiatryonline.com
Textbook of Psychopharmacology >
Chapter 9. Brain–Immune System Interactions: Relevance to the
Pathophysiology and Treatment of Neuropsychiatric Disorders
BRAIN–IMMUNE SYSTEM INTERACTIONS: RELEVANCE TO THE
PATHOPHYSIOLOGY AND TREATMENT OF NEUROPSYCHIATRIC
DISORDERS: INTRODUCTION
Although once considered heresy, the notion that meaningful interactions occur between the brain
and the immune system has become scientific dogma. This change in scientific orthodoxy results
from more than 30 years of research demonstrating that brain-mediated events, such as
psychological stress and depression, can alter peripheral immune system functioning and,
conversely, that changes in peripheral immune functioning, such as those that occur during illness,
can profoundly affect the brain, leading to clinically meaningful changes in mood, anxiety, and
cognition. In this chapter, we provide an overview of brain–immune system interactions that are of
potential relevance to the field of psychiatry.
This effort needs to be understood within the far wider context of psychoneuroimmunology, which
is the interdisciplinary field that focuses on brain–mind–immune system interactions. When Robert
Ader first coined the term psychoneuroimmunology as a title for his textbook on brain–immune
system interactions in 1981, the resulting text filled a single slim volume (Ader 1981). In contrast,
the most recent edition fills two volumes, each running more than 1,000 pages, and covers topics
as diverse as gene–ribonucleic acid interactions within the cellular nucleus and the effects of
spirituality on the immune system (Ader 2007).
THE IMMUNE SYSTEM: AN OVERVIEW
When considered in the broadest sense as the process whereby organisms maintain functional and
organizational integrity against foreign encroachment, immunity is clearly a prerequisite to life
itself. Given this, it is not surprising that even the simplest of organisms demonstrate immune
functioning, which is consistent with the notion that immunity arose early in the evolution of life on
earth (Maier and Watkins 1998). In vertebrates, the immune system has evolved a wide array of
separate, but cooperative, mechanisms that serve to attack invading pathogens, destroy tumor
cells, and remove and repair damaged tissue. From an evolutionary perspective, the high rate of
autoimmune disorders, such as multiple sclerosis and rheumatoid arthritis, suggests that the
adaptive advantages of robust immune system functioning outweigh the frequently disastrous
consequences engendered when the immune system overreacts and begins attacking the self
(Nesse and Williams 1994). The immune system review that follows is necessarily simplified. More
extensive discussions of the immune system can be found elsewhere (Abbas and Lichtman 2004;
Rabin 1999; Roitt et al. 1998).
Innate Versus Acquired Immunity
A primary distinction within the immune system is between innate immunity (also known as natural
or nonspecific immunity) and acquired (or specific) immunity. Innate immunity provides a first line
of defense by attacking foreign substances rapidly in a nonspecific manner, without requiring that a
specific antigen (or antibody-generating molecule) be recognized (Table 9–1). Although this lack of
antigenic specificity precludes the development of an immunological memory to speed the response
should a pathogen be encountered again in the future, the nonselectivity of the innate immune
system allows for a rapid response to a wide variety of environmental assaults. The immediatePrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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response sets in motion a complicated series of processes that contribute to activation of the
acquired immune system, which responds more slowly, but far more selectively, to the particular
invading entity. An acquired immune response requires specific recognition of a foreign substance
and allows for the establishment of memory cells that react far more quickly when the same
substance is again encountered. Finally, both innate and acquired immune systems contain
mechanisms to control and extinguish activation; therefore, immune activity, with its attendant
metabolic costs and danger of self attack, does not become self-perpetuating.
TABLE 9–1. Major divisions of the immune response
Acquired immune response
Innate immune response Cellular response Humoral response
Effector cells Phagocytes (macrophages,
neutrophils), NK cells
Th1 lymphocytes, cytolytic T
lymphocytes
Th2 lymphocytes, B
lymphocytes
Soluble mediators Complement, acute-phase
reactants
Antibodies
Representative
cytokines
TNF- , IL-1 and , IL-6 IL-2, IL-12, IFN-
IL-4, IL-10
Note. IFN = interferon; IL = interleukin; NK = natural killer; Th1 = T-helper 1; Th2 = T-helper 2; TNF =
tumor necrosis factor.
Innate immunity begins with the skin and other mucosal surfaces lining the gastrointestinal and
respiratory tracts, which provide a physiochemical barrier to invasion by foreign pathogens. When
these surfaces are breached, phagocytic cells, such as macrophages, microglia (in the brain), and
certain dendritic cells, recognize invading pathogens through relatively crude pattern-recognition
molecules referred to as toll-like receptors and, depending on the cell type, ultimately engulf and
destroy these foreign agents. Upon activation, these cells and other participants in the early innate
immune response (e.g., natural killer [NK] cells) release soluble, proteinaceous, immune mediators
known as cytokines. Cytokines that mediate innate immunity include the type I interferons, which
have direct antiviral effects, and proinflammatory cytokines. Of these, interleukin-1 (IL-1),
interleukin-6 (IL-6), and tumor necrosis factor– (TNF- ) are important in inducing inflammation at
the site of pathogen invasion or tissue damage. IL-6 also plays a central role in stimulating the liver
to produce a host of acute-phase reactants, such as C-reactive protein; 1-acid glycoprotein;
complement C3; haptoglobin; 2-macroglobulin; 1-antitrypsin; ceruloplasmin; and -, -, and
-fibrinogen (Baumann and Gauldie 1994). These proteins, which make up the acute-phase
response, serve to both facilitate destruction of foreign substances and limit tissue damage from
immune activation. In addition to the release of cytokines and acute-phase proteins, other
molecules are induced, including chemokines and adhesion molecules, which assist in the
recruitment of multiple cell types to the site of infection and/or tissue damage and destruction.
Depending on the magnitude of the innate immune response, relevant cytokines can enter the
peripheral blood or activate local afferent nerve fibers and have potent effects on the
neuroendocrine system, especially the hypothalamic-pituitary-adrenal (HPA) axis and the central
nervous system (CNS), where they mediate many symptoms of illness, including fever, loss of
appetite, social withdrawal, and sleep changes (Maier et al. 1998). These behavioral changes are
believed to subserve the metabolic demands inherent in the task of fighting infection and
maintaining an elevated body temperature.
Acquired immunity relies on hematopoietically derived lymphocytes, which have the ability to
specifically recognize an astoundingly wide array of foreign substances. These lymphocytes fall into
two general categories. T lymphocytes mature in the thymus and mediate cellular immunity, which
is essential for protection against intracellular pathogens, such as viruses and mycobacteria. B
lymphocytes mature in the bone marrow and produce antibodies that are especially effective in
neutralizing bloodborne and extracellular pathogens, such as parasites, viruses in replication
phase, and many species of bacteria. A further key function of the acquired immune system is toPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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screen out lymphocytes that might react against self molecules. When this essential function fails,
autoimmune conditions can result.
Like innate immunity, acquired immunity utilizes soluble cytokine mediators. It is generally
recognized that an acquired immune response develops along one of two lines, Th1 or Th2, on the
basis of the cytokine profiles induced by T-helper CD4 cells (Elenkov and Chrousos 1999). A Th1
response is characterized by cytokines that promote cell-mediated inflammatory reactions, such as
delayed-type hypersensitivity (DTH). These cytokines include interleukin-2 (IL-2), interleukin-12
(IL-12), tumor necrosis factor– (TNF- ), and interferon- (IFN- ). Cytokines generated by
T-helper cells during a Th2 immune response include interleukin-4 (IL-4), interleukin-9 (IL-9), and
interleukin-10 (IL-10). IL-6 is also produced by CD4 cells during a Th2-type acquired immune
response. The development of a Th2 response favors antibody production, may provide protection
against parasites, and is associated with allergic and hypersensitivity reactions.
An acquired immune system response consists of three phases: an induction phase, in which the
system detects the presence of antigen; an activation phase, in which the presence of antigen
triggers the expansion of antigen-specific T and B cells; and an effector phase, in which the foreign
substance is cleared from the body (Miller et al. 2000). In this process, the acquired immune
system utilizes and empowers many innate immune elements. For example, the coating of bacteria
by B cell–produced antibodies enhances the ability of innate immune system phagocytes to destroy
pathogens. Like other complicated physiological response systems, the immune response has
built-in negative feedback elements that have evolved to limit immune reactivity once the
pathogenic challenge has been met. Other bodily systems, including the HPA axis, perform
important extrinsic immunomodulatory roles, and when functioning optimally, these systems limit
inflammation and immune system proliferation. A final feature of the acquired immune system,
which is central to its functioning, is the formation of long-lived B and T lymphocytes that serve as
memory cells for recognizing an antigen should it be encountered in the future. This mechanism
accounts for the ability of acquired immunity to mount far more rapid and effective responses to
previously seen antigens. It also provides the physiological basis for the effectiveness of vaccines,
which activate acquired immunity toward a specific pathogen without inducing illness.
BRAIN TO BODY: CENTRAL NERVOUS SYSTEM EFFECTS ON THE IMMUNE
SYSTEM
Despite the fact that a general belief in the ability of psychological states to affect health has been
apparent since antiquity, scientific formulations, until recently, have tended to view the CNS and
the immune system as separate and noninteracting entities. Indeed, the immune system has
historically been conceptualized as autonomous and self-contained, with a purpose that begins and
ends with the tasks of protection against infection and malignancy and the repair of damaged
tissue. Such a view tends to preclude any physiological mechanism by which mental events might
directly affect immune functioning. However, in the 1970s, researchers made the startling
discovery that the immune system was amenable to classical Pavlovian conditioning (Ader and
Cohen 1975). Numerous studies have confirmed and extended this initial insight and established
beyond argument the ability of brain states to significantly modulate immune system functioning.
The majority of these studies have focused on the effects of stress on the immune response.
Virtually every type of stressor, ranging from laboratory stressors (e.g., public speaking, mental
arithmetic) to more naturalistic stressors (e.g., bereavement, loneliness, and academic
examinations), has demonstrated a measurable effect on the immune response, including effects on
various aspects of both innate and acquired immunity (Raison et al. 2002). Although the
relationship between stress and immunity is quite complex, more acute and/or mild stressors, in
general, tend to be associated with activation of immune responses, whereas more chronic and
intense stressors tend to be associated with activated innate immune system elements and
impaired acquired immune system responses. The health relevance of these stress-related immune
changes has been demonstrated in studies that have shown an association between chronic stress
and increased susceptibility to the common cold, reduced antibody responses to vaccination, and
delayed wound healing (Cohen et al. 1991; Glaser et al. 1992; Kiecolt-Glaser et al. 1995). In Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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addition, stress, as well as depression, has been linked to increased morbidity and mortality in
infectious diseases (e.g., HIV infection), neoplastic diseases (including breast cancer and malignant
melanoma), diabetes, and cardiovascular disease (Evans et al. 2005; Fenton and Stover 2006;
Leserman et al. 1999; Raison and Miller 2003a).
Effects of Depression and Stress on Acquired Immune (Lymphocyte)
Responses
In psychiatry, the practical import of connections between brain outflow pathways and the immune
system has been best documented in the effects of stress-related disorders, especially major
depression, on immune functioning. Despite a significant degree of heterogeneity across individual
studies, significant evidence suggests that patients with major depression demonstrate a number of
immune changes similar to those seen in individuals undergoing chronic and/or severe stress
(Herbert and Cohen 1993; Zorrilla et al. 2001). This is hardly surprising, given the many indices of
stress system hyperactivity that are apparent in patients with major depression, including
increased corticotropin-releasing hormone (CRH) and cortisol production (Pariante et al. 1995) and
augmented sympathetic nervous system (SNS) activity as manifested in part by increased
peripheral blood catecholamines (Veith et al. 1994; Wong et al. 2000). Enumerative immune
changes shared by major depression and chronic/severe stress include a decrease in lymphocytes,
B cells, and T cells and an increase in the ratio of CD4 to CD8 T cell subsets (Herbert and Cohen
1993). Shared functional changes include a decrease in NK cell activity and lymphocyte
proliferation in response to nonspecific mitogens (Herbert and Cohen 1993; Zorrilla et al. 2001).
In a meta-analysis examining the issue, major depression was found to have a larger effect than
stress on these immune variables (Zorrilla et al. 2001) (Table 9–2). It is important to note,
however, that major depression is a heterogeneous condition and that immune changes are not
uniform across all patients. Indeed, inhibited lymphocyte responses tend to be most striking in
patients who are older, are hospitalized, or have more severe and/or melancholic types of
depression (Miller 1998; Schleifer et al. 1989). In addition, the sleep changes common in
depression are known to alter lymphocyte responses, especially NK cell activity (NKCA), even in the
absence of other depressive symptoms (Irwin et al. 1996). Nonetheless, it does not appear that
these factors completely account for the association between major depression and alterations in
measures of the number and function of lymphocyte subsets (Herbert and Cohen 1993).
TABLE 9–2. Immune alterations in major depression
Increased white blood cells
Increased neutrophil percentage
Decreased lymphocyte percentage
Increased CD4-to-CD8 ratio
Decreased natural killer cell activity
Decreased mitogen-induced lymphocyte proliferation
Increased interleukin-6
Increased haptoglobin
Increased prostaglandin E2
Compared with chronic/severe stress, major depression has been less well characterized in terms
of effects on in vivo functional immunity; however, the little evidence that is available suggests that
depression, like chronic/severe stress, may impair T-cell function in ways that are relevant to
disease vulnerability. For example, although it is not known whether major depression is associated
with an increase in antibody titers to latent viruses, one study reports that patients with major
depression have a marked decrease in the ability to generate lymphocytes that respond to the
herpes zoster virus (Irwin et al. 1998). Also consistent with impaired T-cell function in depression
is the observation that depressed patients, especially those with melancholia, demonstratePrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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impaired DTH (Hickie et al. 1993).
Effects of Depression and Stress on Innate Immune Inflammatory
Responses
Although stress and depression have been most often seen as suppressing lymphocyte function,
emerging data suggest that such a conclusion oversimplifies the complexities of the mammalian
immune response to environmental perturbation and that stress indeed may also activate certain
aspects of the immune system (Raison and Miller 2001; Raison et al. 2006). For example, stress
exposure in animals and humans has been shown to increase the expression of innate immune
cytokines (Goebel et al. 2000; Maier and Watkins 1998; Paik et al. 2000), activate microglia (Frank
et al. 2007), and sensitize subsequent immune responses to inflammatory immune challenge
(Johnson et al. 2004). Peripheral production of either IL 1 or its soluble receptor antagonist
(sIL-1ra), as well as IL-6, has been reported to be increased in the context of several acutely
stressful situations, including exercise, academic examinations, and laboratory stressors
(Ackerman et al.1998; Goebel et al. 2000; Maes et al. 1998; Pace et al. 2006; Paik et al. 2000;
Steptoe et al. 2001). While the mechanism by which stress induces cytokine production has yet to
be fully elucidated, it has been shown that catecholamines may play an important role. In
particular, – but not -adrenoreceptors are critical for central production of inflammatory
cytokines, whereas both – and -adrenoreceptors contribute to the induction of plasma cytokines
following stress (Johnson et al. 2005). These effects of stress appear to be mediated in part by
activation of inflammatory signaling pathways including nuclear factor kappa B (NF- B), which is a
linchpin in the initiation of the inflammatory response following the stimulation of toll-like
receptors as well as relevant cytokine receptors (Bierhaus et al. 2003).
A growing database suggests that depression (in addition to stress) in both medically healthy and
medically ill patients is associated with innate immune system activation (Andrei et al. 2007; Kim
et al. 2007; Lesperance et al. 2004; Maes 1999; Musselman et al. 2001b; Raison et al. 2006).
Findings consistent with inflammatory activation in depression include increased plasma and
cerebrospinal fluid (CSF) concentrations of inflammatory cytokines, increased in vitro production of
proinflammatory cytokines from stimulated peripheral blood mononuclear cells, increased
acute-phase proteins (and decreased negative acute-phase proteins), increased chemokines and
adhesion molecules, and increased production of prostaglandins (Kim et al. 2007; Maes 1999;
Raison et al. 2006). Based on meta-analyses, increases in peripheral blood IL-6 and C-reactive
protein are two of the most reliable inflammatory biomarkers associated with depression (Zorrilla
et al. 2001). Indeed, careful studies examining IL-6 across the circadian cycle have shown a
reverse circadian pattern of IL-6 in depressed patients, with markedly elevated levels of this
cytokine compared with control subjects during the morning hours (Alesci et al. 2005).
Interestingly, given the role of IL-6 and C-reactive protein in predicting disease outcome in both
cardiovascular disorders and diabetes (Ridker et al. 2000a, 2000b), as well as data indicating that
inflammation may play a role in cancer (Aggarwal et al. 2006), the relationship between depression
and activation of the innate immune inflammatory response may provide a mechanism that explains
the negative impact of depression on a number of illnesses (Evans et al. 2005). Moreover, immune
activation in major depression may be involved in several of the pathophysiological changes that
are common in the context of depression, including bone loss, insulin resistance, cachexia,
increased body temperature, and hippocampal volume loss (Raison et al. 2006). Interestingly,
activation of innate immune responses following stress and depression may also contribute to
stress- and depression-induced decreases in acquired immune (lymphocyte) responses. For
example, administration of IL-1ra prior to stressor exposure has been found to reduce the
inhibitory impact of stress on antibody production (Moraska et al. 2002).
There are a number of potential factors that may contribute to increased innate immune responses
in depressed patients. One factor that has received special attention is body mass index (BMI). BMI
has been reliably correlated with peripheral markers of inflammation including IL-6, in part related
to the capacity of adipocytes to produce inflammatory cytokines (Schaffler et al. 2007). Relevant in
this regard, an analysis of data from the Third National Health and Nutrition Examination SurveyPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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revealed that after adjustment for a multitude of variables, including BMI, there was a strong
association between major depression and elevated levels of C-reactive protein in men but not
women (Ford and Erlinger 2004). Early life stress is another factor that may be involved. For
example, males with current major depression and increased early life stress exhibited significantly
greater increases in IL-6 and NF- B DNA binding following a psychosocial stressor compared with
control subjects (Pace et al. 2006).
Given the anti-inflammatory properties of glucocorticoids (Rhen and Cidlowski 2005) (see below for
further discussion of the immunological effects of glucocorticoids), it might be expected that
patients with depression who have decreased glucocorticoid sensitivity, as manifested by
nonsuppression of cortisol on the dexamethasone suppression test (DST), would be especially
prone to showing evidence of immune activation. Some evidence suggests that this is indeed the
case. Compared with patients with depression who have normal in vivo glucocorticoid sensitivity,
patients who are DST nonsuppressors demonstrate increased plasma concentrations of the
acute-phase reactant 1-glycoprotein, as well as increased in vitro mitogen-stimulated IL-6
production (Sluzewska 1999). Glucocorticoid resistance, as assessed by the DST, has been
associated with a poor response to antidepressant treatment (Holsboer 2000). Of interest, in light
of the relationship between DST nonsuppression and increased inflammatory activity, findings
suggest that patients with depression who are treatment resistant are more likely than patients
who are treatment responders to show evidence of increased inflammatory activity, including
increased plasma concentrations of acute-phase proteins, IL-6, and the soluble receptor for IL-6
(sIL-6r), which synergistically enhances IL-6 activity (Raison et al. 2006; Sluzewska 1999).
Moreover, depressed patients who exhibit a decrease in unstimulated TNF- during antidepressant
treatment are more likely to respond than those whose TNF- remains elevated (Lanquillon et al.
2000).
Other Psychiatric Disorders and the Immune Response
Some evidence suggests that other stress-related neuropsychiatric conditions may be associated
with immune activation, although these conditions are less well characterized than major
depression. These disorders include posttraumatic stress disorder (PTSD), chronic fatigue
syndrome (CFS), seasonal affective disorder (SAD), and fibromyalgia. Patients with combat-related
PTSD have been reported to demonstrate increased plasma concentrations of IL-1 and increased
CSF concentrations of IL-6 (Baker et al. 2001; Spivak et al. 1997). PTSD following civilian disasters
appears to be associated with elevated plasma concentrations of IL-6 and its soluble receptor
(Maes et al. 1999c). Although not found consistently (Maes et al. 1999c), both severity of
symptoms and duration of illness have been reported to correlate positively with indices of immune
activation in PTSD (Miller et al. 2001; Spivak et al. 1997).
A growing body of literature suggests that patients exposed to early life trauma may be especially
vulnerable to the development of psychophysical disorders (e.g., CFS, fibromyalgia) that are
characterized by complaints of chronic pain, fatigue, and cognitive difficulties of unknown etiology
(Heim et al. 1997). Consistent with this, these disorders have also been associated with evidence of
increased inflammatory activity. For example, it has been reported that both CFS and fibromyalgia
are accompanied by an increase in acute-phase reactants and increased plasma concentrations
and/or peripheral blood mononuclear cell production of proinflammatory cytokines, including IL-1,
IL-6, and TNF- (Borish et al. 1998; Cannon et al. 1999; Gupta et al. 1997; Maes et al. 1999b). Of
note, one report indicates that SAD, a condition with significant symptom overlap with CFS and
fibromyalgia, may be characterized by increased plasma concentrations of IL-6 (Leu et al. 2001).
Finally, although the picture is far less clear, there has been speculation that immune system
activation may contribute to the pathophysiology of psychotic disorders, including schizophrenia,
possibly related to an autoimmune diathesis (Pearce 2001; Rothermundt et al. 2001). Elevated
levels of cytokines and their receptors, including IL-2, sIL-2, and IL-6, have been reported in the
blood and CSF of patients with schizophrenia, and a high level of CSF IL-2 has been found to predict
subsequent schizophrenic relapse (Rothermundt et al. 2001). In a related fashion, considerationPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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has been given to the role of viral infection early in development (Pearce 2001), based on seasonal
birth patterns that have been reliably replicated in large epidemiological studies of patients with
schizophrenia. These findings are consistent with in utero infections of relevant brain structures,
including the hippocampus, during critical periods of development (especially during the second
trimester) (Pearce 2001). Moreover, cross-reactivity between brain antigens and antigens of
infectious agents may contribute not only to schizophrenia but also to the neurological and
psychiatric complications associated with streptococcal infection (i.e., pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infections [PANDAS]) (Snider and Swedo
2000).
MEDIATING PATHWAYS
Underlying the ability of the CNS to affect the immune system is a host of connections between
autonomic and neuroendocrine pathways and immune system elements. Immune cells are able to
directly respond to brain outflow pathways via receptors for small-molecule neurotransmitters,
adrenal and gonadal steroids, hypothalamic-releasing factors, and other neuropeptides (Raison et
- 2002). Specific receptor densities vary among immune cell types, and these variations correlate
with cell sensitivity to a given ligand.
Autonomic Nervous System
It is well known that sympathetic and parasympathetic pathways within the autonomic nervous
system (ANS) interact to maintain homeostasis in a variety of physiological states, including
regulation of the immune response. In addition to expressing receptors for autonomic and
neuroendocrine signaling molecules, immune cells and tissues are innervated by fibers derived
from the ANS, together comprising a neural pathway which can reflexively regulate the immune
response (Czura et al. 2007; Downing and Miyan 2000; Miller 1998; Raison et al. 2002; Sanders and
Kavelaars 2007; Tracey 2002). For example, the sympathetic branch of the ANS sends fibers into
immune tissues in association with the vascular supply. Within tissue parenchyma, these fibers are
associated with vascular smooth muscle cells, where they regulate vascular tone. In addition,
sympathetic nerve terminals have been observed by electron microscopy to exist in close
approximation with lymphocytes and macrophages. Thus, the sympathetic branch of the ANS
appears able to influence the immune system either by changing the vascular tone and blood flow
into lymphoid organs or by directly influencing immune cell function via locally released
neurotransmitters, especially norepinephrine and neuropeptides such as neuropeptide Y, substance
P, vasoactive intestinal peptide, calcitonin gene–related peptide, and CRH, which, in turn, interact
with specific receptors on nearby immune cells (Bellinger et al. 1997; Czura et al. 2007).
Initial conceptualizations of the effect of the SNS on immune functioning tended to view the system
as being primarily immunosuppressive. Catecholamines are well known to diminish NKCA and
nonspecific mitogen-stimulated lymphocyte proliferation and appear to be the primary mediators of
rapid immune changes in humans in response to acute stress paradigms (Raison and Miller 2001).
Many of the immunosuppressive effects of catecholamines result from -adrenergic receptor
activation: blocking the receptor obviates many of the stress-related immune alterations,
especially those that occur in solid immune tissues, such as the spleen (Benschop et al. 1994;
Cunnick et al. 1990; Rabin 1999; Sanders et al. 2007).
However, in recent years, it has become evident that the immune system effects of both
norepinephrine and epinephrine cannot be adequately subsumed under a single rubric of
immunosuppression. Indeed, as noted above, it has become apparent that catecholamines also
have immune-activating effects, given data that catecholamines can stimulate the production of
proinflammatory cytokines, especially IL-6, both in the periphery and in the CNS and activate
inflammatory signaling cascades (Bierhaus et al. 2003; Johnson et al. 2005; Norris and Benveniste
1993; Papanicolaou et al. 1998). The ability of catecholamines to induce inflammation may be
related in part to a “switch” that occurs whereby protein kinase A activation leads to -adrenergic
receptor phosphorylation, which in turn switches -receptor signaling from Gs to Gi. Gi has been
associated with activation of the ras inflammatory signaling cascade (Daaka et al. 1997). Of note,Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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catecholamines also appear to favor the development of Th1 cellular immune responses and
promote the production of the Th1 cytokine IFN- (Kohm and Sanders 2000). Consistent with this,
-adrenergic receptors are found on Th1 CD4 T cells, but not on Th2 cells (Kohm and Sanders 2000).
In addition to immune regulation by the sympathetic branch, the parasympathetic branch of the
ANS has been shown to contribute to the regulation of innate immune responses via an efferent
neural signaling pathway referred to as the cholinergic anti-inflammatory pathway (Tracey 2002).
The existence of this pathway was initially identified in studies showing that stimulation of the
vagus nerve attenuates immune system activation and the physiological signs of septic shock in
response to lipopolysaccharide, a key component of gram-negative bacterial cell walls (Borovikova
et al. 2000). Follow-up studies have determined that vagal release of acetylcholine, which in turn
interacts with the 7 subunit of the nicotinic AChR ( 7 nAChR) on relevant immune cells, is capable
of suppressing production of cytokines, including TNF- , via inhibitory effects on nuclear
translocation of NF- B (Altavilla et al. 2006; Guarini et al. 2003) and activation of Janus kinase
(JAK) 2 signal transducers and activators of transcriptions (STAT) 3 (de Jonge et al. 2005; Pavlov
and Tracey 2005). Subsequent studies have established that cytokine production is inhibited by
efferent vagal pathways in the context of a variety of inflammatory processes, including myocardial
ischemia, hemorrhagic shock, ischemia/reperfusion, and pancreatitis (Altavilla et al. 2006; Guarini
et al. 2003; Mioni et al. 2005; van Westerloo et al. 2006; H. Wang et al. 2004). It also has been
shown that both vagus nerve stimulation and 7nAChR agonists inhibit production of a number of
proinflammatory cytokines, including TNF, IL-1, IL-6, IL-8, and high-mobility group box 1 (HMGB1)
(H. Wang et al. 2004). Of note, a specific nAChR-dependent vagus nerve pathway to the spleen
has been identified that inhibits proinflammatory cytokine production during endotoxemia and
polymicrobial sepsis. Furthermore, both splenectomy and vagotomy interrupt the cholinergic
anti-inflammatory response (Huston et al. 2006). Taken together, these findings suggest that in
addition to effects on cellular signaling, there are anatomical and hard-wired components of the
cholinergic anti-inflammatory pathway.
Hypothalamic-Pituitary-Adrenal Axis
In concert with the ANS, the HPA axis serves as a central component of the mammalian stress
response system. Although glucocorticoids, which represent the final product of HPA axis
activation, have long been viewed as immunosuppressive because of their well-documented ability
to suppress inflammation (largely through protein–protein interactions between the glucocorticoid
receptor and NF B) (Rhen et al. 2005), it is increasingly recognized that HPA axis effects on
immunity are complex (Dhabhar et al. 1995). This complexity arises from the fact that HPA axis
effects on the immune system depend on numerous factors, including the immune compartment
that is assessed, the element of the HPA axis being evaluated (i.e., CRH vs. cortisol), and the
duration and timing relative to the immune response and stressor application. Thus, for example,
glucocorticoids are known to acutely diminish CD4 cell counts in the blood; however, at the same
time, glucocorticoids enhance CD4-mediated DTH reactions in the skin, through their effects on
lymphocyte trafficking (Dhabhar 1998). Moreover, different HPA axis elements demonstrate
divergent immune system effects. For example, the end result of CRH-induced HPA axis activation
is proinflammatory cytokine suppression, and yet studies demonstrate that the direct effect of CRH
on proinflammatory cytokine production may be stimulatory (Labeur et al. 1995; Paez Pereda et al.
1995).
Finally, the effect of glucocorticoids on naturalistic measures of immunity, such as DTH, depends on
both the concentration and the duration of glucocorticoids within the immune compartment under
consideration. Thus, low doses of glucocorticoids applied for brief periods have been shown in
rodents to stimulate DTH, whereas higher (or more protracted) glucocorticoid exposure suppresses
DTH (Dhabhar and McEwen 1999).
CRH applied within the CNS suppresses several measures of immunity, including splenic NKCA,
mitogen-stimulated lymphocyte proliferation, and in vivo and in vitro antibody formation, as well as
T-cell responses to T-cell receptor antibody (Caroleo et al. 1993; Irwin et al. 1988; Labeur et al. Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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1995; Rassnick et al. 1994). CRH-overproducing mice demonstrate a profound decrease in the
number of B cells and severely diminished primary and memory antibody responses (Stenzel-Poore
et al. 1994). These immunosuppressive effects appear to be mediated by stress response outflow
pathways activated by CRH, given that blockade of the SNS abolishes CRH effects on NKCA and
adrenalectomy obviates CRH effects on lymphocyte proliferation (Irwin et al. 1988; Labeur et al.
1995). In addition, the B-cell decreases in CRH-overproducing mice are consistent with the marked
reduction in rodent B cells observed after chronic glucocorticoid exposure (Miller et al. 1994).
In contradistinction to its immunosuppressive properties, CRH has also been shown to enhance
proinflammatory cytokine production in animals and humans when administered peripherally or
within the CNS. Chronic intracerebroventricular administration of CRH to rats leads to induction of
IL-1 messenger RNA (mRNA) in splenocytes, and acute intravenous administration in humans has
been reported to cause a fourfold increase in the induction of IL-1 (Labeur et al. 1995; Schulte et
- 1994). Similarly, the addition of CRH to in vitro mononuclear cell preparations induces the
release of IL-1 and IL-6 (Leu and Singh 1992; Paez Pereda et al. 1995). Both chronic and acute CRH
infusion have also been reported to increase production of the immunoregulatory cytokine IL-2 in
humans and animals (Labeur et al. 1995; Schulte et al. 1994). In addition to potential
proinflammatory activities of CRH within the CNS, peripheral production of CRH has been
demonstrated in inflammatory diseases, such as ulcerative colitis and arthritis, in which it appears
to act as a local proinflammatory agent (Karalis et al. 1997; Nishioka et al. 1996).
Of all neurotransmitters or hormones known to modulate immune functioning, the actions of
glucocorticoids, although complicated, are probably best understood (Raison et al. 2002). Identified
effects of glucocorticoids on the immune (and inflammatory) system include
Modulation of immune cell trafficking throughout the body (Dhabhar et al. 1995)
Modulation of cell death pathways (i.e., apoptosis) (McEwen et al. 1997)
Inhibition of arachidonic acid pathway products (e.g., prostaglandins) that mediate inflammation and
sickness symptoms (e.g., fever) (Goldstein et al. 1992)
Modulation of Th1/Th2 cellular immune response patterns in a manner that inhibits Th1 (cell-mediated)
responses and promotes Th2 (antibody) responses (Elenkov and Chrousos 1999)
Inhibition of T-cell– and NK-cell–mediated cytotoxicity (Raison et al. 2002)
Inhibition of cytokine production and function through interaction of glucocorticoid receptors with
transcription factors (NF- B, in particular), which, in turn, regulate cytokine gene expression and/or the
expression of cytokine-inducible genes (McKay and Cidlowski 1999)
Although, as discussed below, glucocorticoids may actually enhance certain aspects of naturalistic
immune functioning when produced for brief periods at low to moderate doses in the context of
acute and/or mild stress, glucocorticoids, in general, play a primary role in restraining excessive or
prolonged inflammatory activation (Munck 1989). This property has long been exploited by modern
medicine for the treatment of autoimmune and other chronic inflammatory conditions, with the
result that glucocorticoids remain a cornerstone of our anti-inflammatory armamentarium.
Consistent with their pharmacological uses, glucocorticoids have been shown to be essential for
inflammatory regulation in response to immune system activation. For example, neutralization of
endogenous glucocorticoid function results in enhanced pathology and mortality in animals exposed
to lipopolysaccharide, as well as other inflammatory stimulators, such as streptococcal cell wall
antigen or myelin basic protein (Bertini et al. 1988; Sternberg et al. 1989). Similarly, rodents that
have been rendered glucocorticoid deficient by adrenalectomy have markedly increased death rates
following infection with murine cytomegalovirus, an effect that arises from unrestrained activity of
the proinflammatory cytokine TNF- (Ruzek et al. 1999).
BODY TO BRAIN: IMMUNE SYSTEM EFFECTS ON CENTRAL NERVOUS
SYSTEM FUNCTIONING
Immune System to Brain Signaling Pathways
The field of psychoneuroimmunology is based on the existence of bidirectional communication
pathways between the brain and the immune system. This implies that just as the CNS is capable ofPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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modulating immunity, the immune system can alter functioning within the CNS. Although
researchers historically were first interested in pathways by which the brain affects immunity, the
past 10–15 years have seen a groundswell of interest in the ways in which the immune system
contributes to the development of psychopathology.
Underpinning this growing interest is an increasing appreciation for the multiple ways in which
proinflammatory cytokines are able to signal the brain and change CNS function (Table 9–3).
Although the brain was historically considered an “immune privileged” organ, protected from
immune system activity by the blood–brain barrier, it is now clear that cytokines released in the
periphery rapidly affect CNS functioning via at least four pathways that are not mutually exclusive
(Raison et al. 2002). Proinflammatory cytokines injected into the abdominal cavity
(intraperitoneal) have been shown to activate the vagus nerve, resulting in the independent
production of proinflammatory cytokines within the CNS, especially in the hypothalamus and
hippocampus, which are regions of central importance for the regulation of the ANS and emotion
(Maier et al. 1998). Recent studies suggest that in addition to activating the vagus nerve,
proinflammatory cytokines in the blood are able to signal the CNS by entering through “leaky”
regions lacking a fully formed blood–brain barrier, such as the circumventricular organs, and, from
there, to circulate in CSF to other brain regions (Rivest et al. 2000). Bloodborne proinflammatory
cytokines can also communicate with the brain through intermediaries, without themselves
entering the CNS parenchyma, for example, by acting on cells of the brain endothelium or choroid
plexus and inducing the release of secondary messengers, such as prostaglandins and nitric oxide
(Rivest et al. 2000). Finally, active transport across the blood–brain barrier provides another
mechanism by which small quantities of proinflammatory cytokines may gain access to the CNS
(Banks 2006; Banks et al. 1995; Plotkin et al. 1996).
TABLE 9–3. Evidence that cytokines can alter central nervous system function
Cytokines released peripherally have access to the brain.
Passage through leaky regions in the blood–brain barrier (e.g., circumventricular organs)
Active transport
Activation of intermediary cell types (e.g., endothelial cells) that produce relevant second messengers (e.g.,
prostaglandins, nitric oxide)
Transmission of cytokine signals through afferent nerve fibers (e.g., vagus)
A cytokine network exists within the brain.
Glia (especially microglia) and neurons express/produce cytokines and express cytokine receptors
Cytokines have effects on neurotransmitter turnover, neuroendocrine function, synaptic plasticity, and
behavior (sickness behavior).
Once proinflammatory cytokines have gained access to the CNS through any of the routes outlined
above, the inflammatory signal appears to be amplified by a cytokine network within the brain itself
(Quan et al. 1999). It has already been noted that cytokines produced in the periphery stimulate
the production of proinflammatory cytokines, such as IL-1, IL-6, and TNF- , in a number of brain
regions (Dantzer and Kelley 2007; Gatti and Bartfai 1993; Laye et al. 1994; Quan et al. 1999).
Receptors for proinflammatory cytokines are found in the brain, especially in areas that are of
central importance to homeostatic and emotional regulation, such as the hypothalamus and
hippocampus (Benveniste 1998). Among neural cells, activated microglia are capable of producing
significant amounts of proinflammatory cytokines, which, in turn, are potent activators of glial cells
(Schobitz et al. 1994). Of interest, growing evidence suggests that nonimmunological stressors can
induce cytokine expression in the brain, likely due in part to stress-induced activation of microglia
(Frank et al. 2007). These data suggest that CNS cytokine pathways may participate in the
response of an organism to a wide variety of environmental perturbations. Consistent with this
finding, proinflammatory cytokines have been implicated in the modulation of circadian functioning,
especially the sleep–wake cycle (Hohagen et al. 1993; Opp 2005).Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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Sickness Behavior and the Development of Depression in the Medically Ill
It has long been known that rates of major depression, as well as milder forms of mood
disturbance, are many times more common in people with medical illnesses than in the general
population (Evans et al. 1999). Although this has been typically ascribed to the overwhelming
psychological stress frequently engendered by being seriously ill, more recent attention has been
paid to the idea that immune system activation, which typically accompanies medical illness, may
itself biologically predispose patients to depression (Raison and Nemeroff 2000). Evidence for this
comes from the observation that rates of depression are significantly elevated in a wide variety of
medical conditions including inflammatory and autoimmune disorders such as multiple sclerosis and
rheumatoid arthritis, as well as illnesses such as cardiovascular disease, diabetes, and cancer,
which are increasingly being recognized as having an important inflammatory component
(Aggarwal et al. 2006; Blake and Ridker 2002; Evans et al. 2005). Moreover, prospective studies of
conditions that are characterized by episodic immune dysregulation, such as multiple sclerosis or
herpes infection, typically find that depression immediately precedes, rather than follows, episodes
of disease exacerbation, suggesting that depressive symptoms associated with these conditions
may result from underlying immune system activity rather than arising from a psychological
reaction to exacerbation of the illness (Foley et al. 1992; Hickie and Lloyd 1995). Finally, as noted
above, numerous groups have shown that when compared with similar patients without a current
mood disorder, plasma concentrations of proinflammatory cytokines are significantly higher in
medically ill patients with major depression versus those without (Raison et al. 2006). For example,
IL-6 is elevated in depressed patients with cancer (Musselman et al. 2001b), and C-reactive protein
is elevated in depressed patients with both acute coronary syndromes and chronic heart failure
(Andrei et al. 2007; Lesperance et al. 2004).
More direct evidence that inflammatory processes may contribute to psychopathology, especially in
the context of medical illness, comes from many studies in humans and animals demonstrating that
the administration of proinflammatory cytokines reliably induces changes in mood, cognition, and
behavior similar to those commonly observed in patients with mood and anxiety disorders, as well
as in psychophysical conditions such as CFS and fibromyalgia (Dantzer and Kelley 2007; Raison et
- 2006). This constellation of immune-induced changes, alternately referred to as “sickness
syndrome” or “sickness behavior,” consists of dysphoria, anhedonia, fatigue, social withdrawal,
hyperalgesia, and cognitive and sleep disturbances, as well as decreases in appetite and libido
(Kent et al. 1992). Although seen in response to infection, the full syndrome can be reproduced in
animals and humans by administration of innate immune cytokines, such as IFN- , IL-1, TNF- , and
IL-6, as well as IL-2, even in the absence of infection (Raison et al. 2002).
Results from studies utilizing positron emission tomography (PET) and functional magnetic
resonance imaging (fMRI) provide further evidence that peripheral cytokine activity can induce
centrally mediated behavioral changes. These and other imaging modalities provide a means by
which various behavioral alterations can be associated with specific brain regions. For example,
during an fMRI task of visuospatial attention, in comparison with control subjects, patients
administered IFN- exhibited significantly greater activation of the dorsal anterior cingulate cortex
(dACC) that highly correlated with the number of task-related errors (Capuron et al. 2005).
Interestingly, increased dACC activity during cognitive tasks has also been demonstrated in
patients vulnerable to mood disorders, such as those with high trait anxiety, neuroticism, or
obsessive-compulsive disorder (Capuron et al. 2005). IFN- has also been shown to lead to changes
in basal ganglia metabolic activity as measured by PET that resemble those seen in Parkinson’s
disease. These changes also correlate with IFN- –induced fatigue-related symptoms and may be a
function of IFN- effects on dopamine metabolism (Capuron et al. 2007).
Blocking cytokine activity with an IL-1 receptor antagonist, -melanocyte-stimulating hormone, or
IL-10 diminishes or prevents the development of sickness behavior in laboratory animals, even
when such behavior develops as a result of psychological stress (Milligan et al. 1998). Similarly,
etanercept, a novel agent that blocks TNF- activity, has been reported to improve energy and
overall emotional functioning in patients with rheumatoid arthritis, a condition characterized byPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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increased proinflammatory cytokine activity (Mathias et al. 2000). Recently TNF antagonists have
been shown to reduce depressive symptoms in patients with several autoimmune conditions
(Persoons et al. 2005; Tyring et al. 2006). Further evidence that cytokine-induced behavioral
toxicity is related to major depression comes from studies showing that in humans and animals,
antidepressants are able to abolish or attenuate the development of sickness behavior in response
to cytokine administration (Musselman et al. 2001a; Yirmiya et al. 2001).
Pathways by Which Inflammatory Cytokines Produce Neuropsychiatric
Disturbance
In keeping with the observation that antidepressants mitigate emotional and behavioral symptoms
resulting from immune system activation, significant evidence demonstrates that inflammatory
cytokines affect neurotransmitters and neuroendocrine pathways that are regulated by currently
available antidepressants and that have been implicated in the pathophysiology of depression and
other stress-related neuropsychiatric disorders. It is increasingly recognized that these effects on
the CNS and its outflow pathways may provide a physiological basis for the observation that
immune activation frequently produces neuropsychiatric disturbance (Table 9–4).
TABLE 9–4. Potential mechanisms by which cytokines may influence behavior
Activation of corticotropin-releasing hormone pathways
Alteration of monoamine metabolism
Induction of the euthyroid sick syndrome
Disruption of glucocorticoid receptor signaling
Alteration of regional brain activity
Inhibition of relevant growth factors
Effects on Monoamine Neurotransmitters
In laboratory animals, the acute intracerebral administration of IL-1 produces a rapid and
significant increase in norepinephrine and serotonin (5-HT) turnover in several brain regions
(Linthorst et al. 1995a, 1995b). Far less is known about the effect of chronic proinflammatory
cytokine exposure on functioning of monoamine systems in either animals or humans; however,
cytokines, including IFN- , have been shown to diminish 5-HT availability as a result of a
cytokine-mediated enhancement in the activity of indoleamine 2,3-dioxygenase (IDO), an enzyme
that shunts tryptophan metabolism away from 5-HT toward kynurenine and quinolinic acid, which is
known to have neurotoxic properties (Dantzer et al. 2007; Raison et al. 2006). Tryptophan is the
primary precursor of 5-HT, and depletion of tryptophan has been associated with the precipitation
of mood disturbances in vulnerable patients (Moore et al. 2000). Moreover, significant evidence
suggests that serotonergic neurotransmission is decreased in many patients with depression
(Owens and Nemeroff 1998). It has also been shown that proinflammatory cytokines, via p38
mitogen-activated protein kinase (MAPK)–linked pathways, can increase the expression and
function of synaptic reuptake pumps for serotonin (and norepinephrine), potentially further
contributing to reduced synaptic availability of mood-relevant monoamines (Zhu et al. 2005, 2006).
Of interest, the development of major depression in the context of chronic IFN- treatment has
been shown to correlate closely with decreased plasma concentrations of tryptophan, possibly as a
result of increased IDO activity, consistent with the idea that cytokine-induced decrements in 5-HT
availability may contribute to the development of depression (Capuron et al. 2002b). Furthermore,
treatment with paroxetine attenuates the behavioral consequences of IFN- –mediated tryptophan
depletion (Capuron et al. 2003a). In addition to the effects of chronic cytokine exposure on
serotonergic transmission, both IL-2 and IFN- , when they are administered chronically, have been
reported to alter dopamine metabolism, and as noted above, IFN- has been shown to lead to
altered metabolic activity in brain regions high in dopaminergic neurocircuits including the basal
ganglia (Capuron et al. 2007; Lacosta et al. 2000; Shuto et al. 1997).Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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Effects on the Thyroid Axis
Medical illness is often associated with a state of functional thyroid deficiency known as euthyroid
sick syndrome (ESS) (Papanicolaou 2000). In its early stages, ESS is characterized by normal
thyroid-stimulating hormone (TSH) and thyroxine (T4) levels, but by reduced levels of
triiodothyronine (T3), which is the more biologically active form of thyroid hormone. In later stages
of ESS, T4 levels are also decreased. Evidence suggests that proinflammatory cytokines promote
this condition via direct effects on the thyroid gland, as well as by inhibition of enzymes responsible
for peripheral conversion of T4 to T3, especially in the liver (Papanicolaou 2000). It is well known
that decreased thyroid functioning is associated with the development of symptoms of depression,
and functional abnormalities of the thyroid axis are observed in many patients with major
depression who do not have clinically obvious thyroid disease (Musselman and Nemeroff 1996).
Effects on the Hypothalamic-Pituitary-Adrenal Axis
Inflammatory cytokines have well-described effects on the HPA axis that are consistent with
changes frequently seen in patients with major depression, including increased production of CRH
and cortisol and decreased tissue sensitivity to glucocorticoid hormones (Capuron et al. 2003a;
Hasler et al. 2004; Pace et al. 2007; Silverman et al. 2005). Although cytokines have been shown to
be capable of activating the HPA axis at multiple levels, with a resultant increase in glucocorticoid
release, significant evidence suggests that a major final common pathway for cytokine activation
involves stimulation of CRH production in the paraventricular nucleus (PVN) of the hypothalamus
(Besedovsky and del Rey 1996). Several lines of evidence suggest that this increase in CRH activity
may contribute to cytokine-induced depression/sickness behavior. CRH has behavioral effects in
animals that are similar to those seen in patients with depression and/or sickness syndrome,
including alterations in appetite, activity, and sleep (Owens and Nemeroff 1991). Patients with
major depression frequently demonstrate increased CRH production, as assessed by increased CRH
in CSF, increased messenger RNA in the PVN, downregulated frontal CRH receptors, and a blunted
adrenocorticotropic hormone (ACTH) response to CRH challenge (likely reflecting downregulation of
pituitary CRH receptors) (Owens and Nemeroff 1993). Agents that block the CRH type I receptor
have been shown to have antidepressant and anxiolytic effects in humans (Zobel et al. 2000). In
animals, blocking CRH reverses some of the behavioral sequelae of proinflammatory cytokine
administration (Dantzer 2001). Indirect evidence for a role of CRH in cytokine-induced depression
in humans comes from a study in which individuals who developed depression during IFN
administration exhibited significantly higher ACTH and cortisol responses to the first injection of
IFN- compared with control subjects (Capuron et al. 2003b). These findings suggest that
sensitized CRH pathways may serve as a vulnerability factor for cytokine-induced behavioral
changes.
In addition to direct stimulatory effects on CRH within the CNS, in vivo and in vitro studies suggest
that inflammation may induce resistance to circulating glucocorticoids in nervous, endocrine, and
immune system tissues (Pariante and Miller 2001; Raison and Miller 2003b). This is of great
potential relevance, given the high rates of relative glucocorticoid resistance in HPA axis tissues (as
assessed in vivo by the DST or the dexamethasone–CRH stimulation test) and the immune system
(as measured in vitro) seen in patients with major depression and in animals and humans exposed
to chronic and/or severe stressors (Holsboer 2000). Supporting a role for cytokines in the induction
of glucocorticoid resistance is the observation that many chronic inflammatory conditions, including
steroid-resistant asthma, rheumatoid arthritis, multiple sclerosis, and HIV infection, are
characterized by a decrease in sensitivity to glucocorticoids (Raison et al. 2002). In HIV infection,
glucocorticoid resistance has been shown to correlate with increased IFN- plasma levels (Norbiato
et al. 1998).
There are several mechanisms by which proinflammatory cytokines can disrupt glucocorticoid
receptor (GR) function and contribute to glucocorticoid resistance. In addition to downregulating
the expression of GR protein, proinflammatory cytokines have been found to increase the
expression of the inert isoform of the GR (Oakley et al. 1996). Exposure of cells thatPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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constitutively express both GR- (the active isoform) and GR- to either TNF- or IL-1 in vitro
results in a marked increase in GR- production, which is associated with the development of
glucocorticoid resistance, as evidenced by a significant reduction in dexamethasone-stimulated
activity of a GR-sensitive reporter gene in cytokine-treated cells (Webster et al. 2001). That
overproduction of the negative GR- isoform has a clinically relevant effect on glucocorticoid
sensitivity is suggested by several recent studies documenting that patients with a variety of
inflammatory and immune system disorders, including asthma, ulcerative colitis, and chronic
lymphocytic leukemia, whose conditions are resistant to steroid treatment demonstrate a
significantly increased GR- to GR- ratio (Honda et al. 2000; Leung 1997; Shahidi et al. 1999;
Sousa et al. 2000).
Another mechanism by which inflammatory cytokines may attenuate GR signal transduction and,
hence, cause glucocorticoid resistance is through induction of inflammatory signaling pathways that
directly influence GR function (Pace et al. 2007). For example, adding IL 1 to an in vitro
preparation of mouse fibroblast cells has been shown to suppress the ability of dexamethasone to
induce translocation of the GR from the cytoplasm to its site of action in the nucleus (Pariante et al.
1999). This IL-1 –mediated blockade of GR translocation from the cytoplasm to the cellular nucleus
inhibits GR activity, as indicated by a decrease in the ability of dexamethasone to activate a
glucocorticoid-sensitive reporter gene construct. The signaling pathways involved in this effect
include p38 MAPK, which has been shown to phosphorylate the GR (X. Wang et al. 2004). Other
inflammatory signaling pathways have also been shown to alter GR function, including NF- B, Jun
N-terminal kinase (JNK), and STAT5 (Pace et al. 2007).
PSYCHOPHARMACOLOGICAL IMPLICATIONS OF BRAIN–IMMUNE SYSTEM
INTERACTIONS
Antidepressants and Immune System Activation
The term antidepressant has been depicted, more than once, as a misnomer, given the wide
spectrum of activity evinced by these pharmacological agents. Adding to this activity spectrum are
findings that antidepressants have clear immunomodulatory effects in animals and humans. In
general, antidepressants have been found to decrease immune responsiveness (Kenis and Maes
2002). Because of this, these agents may be of benefit for a wide range of symptoms that arise in
the context of immune activation. Of special interest, given the ability of inflammatory cytokines to
induce sickness behavior and/or major depression, a number of antidepressants have been
reported to attenuate proinflammatory cytokine production, not just from peripheral immune cells
(Maes 1999) but also from within the CNS, where desipramine has been reported to diminish TNF
release within the locus coeruleus (Ignatowski and Spengler 1994). Interestingly in this regard, the
antidepressant efficacy of desipramine during the forced-swim test has been shown to be
dependent on reductions in neuronal production of TNF- and can be reversed by exogenous TNF
coadministered with the antidepressant (Reynolds et al. 2004). Desipramine has also been shown
to lower peripheral TNF- production in response to lipopolysaccharide (LPS) administration—an
effect that was associated with abrogation of the depressive-like behavioral effects of LPS (Shen et
- 1999). The heterocyclic antidepressant bupropion has been similarly noted to markedly diminish
TNF- production following LPS administration in animals (Brustolim et al. 2006). Of note,
concomitant with attenuating proinflammatory cytokine production, antidepressants enhance
production of the anti-inflammatory cytokine IL-10 (Maes et al. 1999d).
In addition to potential direct effects on cytokine production, antidepressants impact
neuroendocrine and neurotransmitter systems in ways known to diminish inflammatory activity. For
example, all antidepressants appear to downregulate the overproduction of CRH and cortisol that
frequently occurs in the context of major depression. Much evidence suggests that this
downregulation results from the ability of antidepressants to enhance glucocorticoid signaling via
increased glucocorticoid receptor functioning, which, in turn, leads to a restoration of
glucocorticoid-mediated inhibitory control on the HPA axis (Pariante and Miller 2001). Because CRH
has been shown to directly stimulate proinflammatory cytokine production, antidepressants may
modulate inflammatory activity in part by diminishing CRH production. Glucocorticoid receptors, inPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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addition to inhibiting CRH release in the hypothalamus, also mediate the well-characterized
anti-inflammatory properties of glucocorticoids. It is likely that antidepressants decrease
inflammatory activity in part via their ability to potentiate glucocorticoid receptor functioning
(Pariante and Miller 2001). Antidepressants also normalize the hyperactivity of the locus coeruleus
and SNS frequently seen in major depression (Ressler and Nemeroff 1999). Because
catecholamines have been shown to enhance proinflammatory activity, the ability of
antidepressants to normalize catecholaminergic functioning would be expected to diminish
inflammatory activity. Finally, antidepressants are known to enhance functioning in intracellular
second-messenger systems (such as the cyclic adenosine monophosphate [cAMP] cascade) known
to suppress the activation of genes that encode for the production of proinflammatory cytokines
(Duman et al. 2001).
Whatever the mechanism, it is clear from studies in animals and humans that antidepressants
effectively diminish many physical, emotional, cognitive, and behavioral symptoms that arise in the
context of immune system activation (Capuron et al. 2002a). In animals, pretreatment with a
number of antidepressants has been shown to prevent or diminish the development of sickness
syndrome in response to either pathogen or cytokine exposure (Yirmiya et al. 2001). In humans,
pretreatment with an antidepressant has been shown in a double-blind, placebo-controlled trial to
significantly reduce the development of major depression in patients receiving high doses of the
proinflammatory cytokine IFN- for the treatment of malignant melanoma (Musselman et al.
2001a). In this study, 45% of patients receiving placebo had developed major depression within 3
months of starting IFN- , compared with only 11% receiving the selective serotonin reuptake
inhibitor paroxetine. Of interest, however, paroxetine was not equally efficacious for all the
symptoms associated with sickness syndrome. Specifically, the antidepressant significantly reduced
the symptoms of depressed mood, anxiety, and poor cognitive functioning but was no more
effective than placebo in the treatment of somatic or neurovegetative symptoms, such as fatigue
and anorexia, suggesting that these symptom domains may have nonoverlapping etiologies
(Capuron et al. 2002a). Consistent with this finding, neurovegetative symptoms tended to develop
early (and to persist) in the course of IFN- treatment in a majority of patients, whereas symptoms
of depressed mood, anxiety, and cognitive disturbance tended to develop insidiously over weeks or
months of treatment in a smaller percentage of patients (Trask et al. 2000). The success of
pretreatment strategies in preventing the development of neuropsychiatric disorders in medically ill
patients at high risk for mood disorders is intriguing and suggests that prophylactic antidepressants
may be considered in other medical contexts, such as for patients about to undergo treatment with
radiation and/or chemotherapy, as well as for patients about to undergo major surgery.
There are also data to suggest that antipsychotics, although not as well studied as antidepressants,
may have immunological effects relevant to their mechanism of action. Intriguing in this regard is a
study demonstrating increased antipsychotic efficacy in patients with schizophrenia treated with
the combination of the cyclo-oxygenase-2 inhibitor celecoxib, an anti-inflammatory drug, and
risperidone versus risperidone plus placebo (Müller et al. 2002).
Immune System Interventions for Behavioral Symptoms
Given that proinflammatory cytokines induce depressive syndromes, and given that many medically
healthy patients with depression appear to demonstrate increased inflammatory activity, it is
logical to inquire as to whether agents that directly target inflammatory mediators, such as
anti-inflammatory agents and drugs that disrupt cytokines and their cytokine signaling pathways
(e.g., NF- B, p38 MAPK), might be of benefit in the treatment of both stress- and immune-related
neurobehavioral disorders. Indeed, in a recent double-blind, randomized, placebo-controlled study,
patients with major depressive disorder who took celecoxib as an adjunct to reboxetine
experienced a significantly greater therapeutic benefit than those taking reboxetine alone (Müller
et al. 2006). In animal models, endogenous inhibitors of proinflammatory cytokines, such as the
soluble receptor antagonist for IL-1 (sIL-1ra), have been reported to attenuate or abolish sickness
symptoms following endotoxin or cytokine administration (Maier and Watkins 1998). Of interest, in
addition to direct anti-inflammatory activities, sIL-1ra also blocks many of the sequelae ofPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
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psychological stress in rodents. For example, direct injection of sIL-1ra blunts HPA axis responses
to psychological stressors, such as restraint, and prevents stress from causing learned helplessness
(a frequent animal model for depression) (Maier and Watkins 1998). Administration of IL-ra has
also been shown to reverse the inhibitory effects of stress on the expression of brain-derived
neurotrophic factor in the dentate gyrus of the rat hippocampus (Barrientos et al. 2003). Of note,
mice whose TNF- receptor genes have been knocked out exhibit an antidepressant phenotype and
are resistant to anxiety-conditioning paradigms and virus-induced anxiety behaviors (Silverman et
- 2004, 2007; Simen et al. 2006). Of further relevance to the behavioral effects of targeting
cytokines such as TNF- are data demonstrating improvements in behavioral symptoms in patients
with inflammatory and autoimmune disorders who are receiving therapies that block TNF- activity
(e.g., etanercept, infliximab). For example, significant improvement in emotional well-being has
been observed in patients treated with these agents for psoriasis, rheumatoid arthritis, and
ankylosing spondylitis (Braun et al. 2007; Katugampola et al. 2007; Mathias et al. 2000). Most
relevant, however, was a recent double-blind, placebo-controlled trial of etanercept for the
treatment of psoriasis, in which patients who received active drug exhibited significantly greater
improvement in depressive symptoms compared with placebo-treated patients, independent of the
effect of the drug on disease activity (Tyring et al. 2006). Although the risk of side effects with
cytokine antagonists is relatively low, when adverse events do occur, they can be serious, including
life-threatening infections, reactivation of tuberculosis, congestive heart failure, lymphoma,
induction of autoantibodies, and a lupus-like reaction.
Treatment of chronic pain, with or without the presence of mood symptoms, is another burgeoning
area of translational drug discovery. Data from animal models suggest that proinflammatory
cytokines, specifically IL-1 and TNF, play a pivotal role in the creation and maintenance of
neuropathic pain (Marchand et al. 2005; Moalem and Tracey 2006). These findings led to the
hypothesis that IL-10, an anti-inflammatory cytokine, may prove to be a promising therapeutic
option via attenuation of IL-1 and TNF activity. Indeed, it has been shown in animal studies that
IL-10, via intrathecal IL-10 gene therapy, is effective in the control of both acute and chronic pain
(Ledeboer et al. 2007; Milligan et al. 2006).
It has been suggested that the increased prevalence of major depression observed in the Western
world over the past half-century may be caused, at least in part, by a decrease in the consumption
of omega-3 fatty acids (Maes et al. 1999a), which are well known to have anti-inflammatory effects
via the inhibition of prostaglandins and proinflammatory cytokines. Consistent with this,
populations that consume diets high in omega-3 fatty acids (found especially in fish) appear to
have diminished rates of major depression (Tanskanen et al. 2001). Conversely, patients with
major depression have been reported to have decreased serum concentrations of omega-3 fatty
acids (Maes et al. 1999a; Tiemeier et al. 2003). These observations suggest that the administration
of omega-3 fatty acids might be beneficial to patients with mood disorders. Preliminary studies
have indeed shown that adjunctive administration of omega-3 fatty acids under double-blind,
placebo-controlled conditions significantly improves persistent mood symptoms in patients with
depression (Peet and Horrobin 2002) and decreases disease relapse in patients with bipolar
disorder (Stoll et al. 1999). Low omega-3 fatty acid levels may also contribute to the increased
rates of depression in the medically ill, in particular in patients with cardiovascular disease. In a
study evaluating patients 2 months after an acute coronary event (myocardial infarction or unstable
angina), patients with comorbid major depression had significantly lower levels of omega-3 fatty
acids (Frasure-Smith et al. 2004) than their nondepressed counterparts. Given that low omega-3
fatty acid levels are associated with mood disorders (Parker et al. 2006), in addition to increased
levels of inflammation (Simopoulos 2002), an increased risk for coronary artery disease
(Kris-Etherton et al. 2003), and fatal arrhythmias (Leaf et al. 2003), further studies evaluating the
effects of omega-3 supplements in at-risk populations are warranted.
REFERENCES
Abbas AK, Lichtman AH: Basic Immunology: Functions and Disorders of the Immune System, 2nd
Edition. Philadelphia, PA, WB Saunders, 2004Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
17 of 27
10/05/2009 15:52
Ackerman KD, Martino M, Heyman R, et al: Stressor-induced alteration of cytokine production in
multiple sclerosis patients and controls. Psychosom Med 60:484–491, 1998 [PubMed]
Ader R: Psychoneuroimmunology. New York, Academic Press, 1981
Ader R: Psychoneuroimmunology, 4th Edition. Burlington, MA, Elsevier Academic Press, 2007
Ader R, Cohen N: Behaviorally conditioned immunosuppression. Psychosom Med 37:333–340, 1975
[PubMed]
Aggarwal BB, Shishodia S, Sandur SK, et al: Inflammation and cancer: how hot is the link? Biochem
Pharmacol 72:1605–1621, 2006 [PubMed]
Alesci S, Martinez PE, Kelkar S, et al: Major depression is associated with significant diurnal
elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological
complexity in its secretion: clinical implications. J Clin Endocrinol Metab 90:2522–2530, 2005
[PubMed]
Altavilla D, Guarini S, Bitto A, et al: Activation of the cholinergic anti-inflammatory pathway reduces
NF-kappab activation, blunts TNF-alpha production, and protects against splanchic artery occlusion
shock. Shock 25:500–506, 2006 [PubMed]
Andrei AM, Fraguas R Jr, Telles RM, et al: Major depressive disorder and inflammatory markers in
elderly patients with heart failure. Psychosomatics 48:319–324, 2007 [Full Text] [PubMed]
Baker DG, Ekhator NN, Kasckow JW, et al: Plasma and cerebrospinal fluid interleukin-6
concentrations in posttraumatic stress disorder. Neuroimmunomodulation 9:209–217, 2001
[PubMed]
Banks WA: The blood-brain barrier in psychoneuroimmunology. Neurol Clin 24:413–419, 2006
[PubMed]
Banks WA, Kastin AJ, Broadwell RD: Passage of cytokines across the blood-brain barrier.
Neuroimmunomodulation 2:241–248, 1995 [PubMed]
Barrientos RM, Sprunger DB, Campeau S, et al: Brain-derived neurotrophic factor mRNA
downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor
antagonist. Neuroscience 121:847–853, 2003 [PubMed]
Baumann H, Gauldie J: The acute phase response (comments). Immunol Today 15:74–80, 1994
[PubMed]
Bellinger DL, Felten SY, Lorton D, et al: Innervation of the lymphoid organs and
neurotransmitter–lymphocyte interactions, in Immunology of the Nervous System. Edited by Keane
RW, Hickey WF. New York, Oxford University Press, 1997, pp 226–332
Benschop RJ, Nieuwenhuis EE, Tromp EA, et al: Effects of beta-adrenergic blockade on immunologic
and cardiovascular changes induced by mental stress. Circulation 89:762–769, 1994 [PubMed]
Benveniste EN: Cytokine actions in the central nervous system. Cytokine Growth Factor Rev
9:259–275, 1998 [PubMed]
Bertini R, Bianchi M, Ghezzi P: Adrenalectomy sensitizes mice to the lethal effects of interleukin 1
and tumor necrosis factor. J Exp Med 167:1708–1712, 1988 [PubMed]
Besedovsky HO, del Rey A: Immune-neuro-endocrine interactions: facts and hypotheses. Endocrinol
Rev 17:64–102, 1996 [PubMed]
Bierhaus A, Wolf J, Andrassy M, et al: A mechanism converting psychosocial stress into
mononuclear cell activation. Proc Natl Acad Sci U S A 100:1920–1925, 2003 [PubMed]
Blake GJ, Ridker PM: Tumour necrosis factor-alpha, inflammatory biomarkers, and atherogenesis.
Eur Heart J 23:345–347, 2002 [PubMed]Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
18 of 27
10/05/2009 15:52
Borish L, Schmaling K, DiClementi JD, et al: Chronic fatigue syndrome: identification of distinct
subgroups on the basis of allergy and psychologic variables. J Allergy Clin Immunol 102:222–230,
1998 [PubMed]
Borovikova LV, Ivanova S, Zhang M, et al: Vagus nerve stimulation attenuates the systemic
inflammatory response to endotoxin. Nature 405:458–462, 2000 [PubMed]
Braun J, McHugh N, Singh A, et al: Improvement in patient-reported outcomes for patients with
ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly.
Rheumatol (Oxf) 46:999–1004, 2007 [PubMed]
Brustolim D, Ribeiro-dos-Santos R, Kast RE, et al: A new chapter opens in anti-inflammatory
treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and
interferon-gamma in mice. Int Immunopharmacol 6:903–907, 2006 [PubMed]
Cannon JG, Angel JB, Ball RW, et al: Acute phase responses and cytokine secretion in chronic
fatigue syndrome. J Clin Immunol 19:414–421, 1999 [PubMed]
Capuron L, Gumnick JF, Musselman DL, et al: Neurobehavioral effects of interferon-alpha in cancer
patients: phenomenology and paroxetine responsiveness of symptom dimensions.
Neuropsychopharmacology 26:643–652, 2002a
Capuron L, Ravaud A, Neveu PJ, et al: Association between decreased serum tryptophan
concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol
Psychiatry 7:468–473, 2002b
Capuron L, Neurauter G, Musselman DL, et al: Interferon-alpha-induced changes in tryptophan
metabolism: relationship to depression and paroxetine treatment. Biol Psychiatry 54:906–914,
2003a
Capuron L, Raison CL, Musselman DL, et al: Association of exaggerated HPA axis response to the
initial injection of interferon-alpha with development of depression during interferon-alpha
therapy. Am J Psychiatry 160:1342–1345, 2003b
Capuron L, Pagnoni G, Demetrashvili M, et al: Anterior cingulate activation and error processing
during interferon-alpha treatment. Biol Psychiatry 58:190–196, 2005 [PubMed]
Capuron L, Pagnoni G, Demetrashvili MF, et al: Basal ganglia hypermetabolism and symptoms of
fatigue during interferon-alpha therapy. Neuropsychopharmacology 32:2384–2392, 2007 [PubMed]
Caroleo MC, Pulvirenti L, Arbitrio M, et al: Evidence that CRH microinfused into the locus coeruleus
decreases cell-mediated immune response in rats. Funct Neurol 8:271–277, 1993 [PubMed]
Cohen S, Tyrrell DA, Smith AP: Psychological stress and susceptibility to the common cold
(comments). N Engl J Med 325:606–612, 1991 [PubMed]
Cunnick JE, Lysle DT, Kucinski BJ, et al: Evidence that shock-induced immune suppression is
mediated by adrenal hormones and peripheral beta-adrenergic receptors. Pharmacol Biochem
Behav 36:645–651, 1990 [PubMed]
Czura CJ, Rosas-Ballina M, Tracey KJ: Cholinergic regulation of inflammation, in
Psychoneuroimmunology, 4th Edition. Edited by Ader R. Burlington, MA, Elsevier Academic Press,
2007, pp 85–96
Daaka Y, Luttrell LM, Lefkowitz RJ: Switching of the coupling of the beta2-adrenergic receptor to
different G proteins by protein kinase A. Nature 390:88–91, 1997 [PubMed]
Dantzer R: Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 15:7–24,
2001 [PubMed]
Dantzer R, Kelley KW: Twenty years of research on cytokine-induced sickness behavior. Brain
Behav Immun 21:153–160, 2007 [PubMed]Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
19 of 27
10/05/2009 15:52
de Jonge WJ, van der Zanden EP, The FO, et al: Stimulation of the vagus nerve attenuates
macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 6:844–851,
2005
Dhabhar FS: Stress-induced enhancement of cell-mediated immunity. Ann N Y Acad Sci
840:359–372, 1998 [PubMed]
Dhabhar FS, McEwen BS: Enhancing versus suppressive effects of stress hormones on skin immune
function. Proc Natl Acad Sci U S A 96:1059–1064, 1999 [PubMed]
Dhabhar FS, Miller AH, McEwen BS, et al: Effects of stress on immune cell distribution. Dynamics
and hormonal mechanisms. J Immunol 154:5511–5527, 1995 [PubMed]
Downing JE, Miyan JA: Neural immunoregulation: emerging roles for nerves in immune homeostasis
and disease. Immunol Today 21:281–289, 2000 [PubMed]
Duman RS, Nakagawa S, Malberg J: Regulation of adult neurogenesis by antidepressant treatment.
Neuropsychopharmacology 25:836–844, 2001 [PubMed]
Elenkov IJ, Chrousos G: Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and
susceptibility to disease. Trends Endocrinol Metab 10:359–368, 1999 [PubMed]
Evans DL, Staab JP, Petitto JM, et al: Depression in the medical setting: biopsychological
interactions and treatment considerations. J Clin Psychiatry 60 (suppl 4):40–55; discussion 56,
1999
Evans DL, Charney DS, Lewis L, et al: Mood disorders in the medically ill: scientific review and
recommendations. Biol Psychiatry 58:175–189, 2005 [PubMed]
Fenton WS, Stover ES: Mood disorders: cardiovascular and diabetes comorbidity. Curr Opin
Psychiatry 19:421–427, 2006 [PubMed]
Foley FW, Traugott U, LaRocca NG, et al: A prospective study of depression and immune
dysregulation in multiple sclerosis. Arch Neurol 49:238–244, 1992 [PubMed]
Ford DE, Erlinger TP: Depression and C-reactive protein in US adults: data from the Third National
Health and Nutrition Examination Survey. Arch Intern Med 164:1010–1014, 2004 [PubMed]
Frank MG, Baratta MV, Sprunger DB, et al: Microglia serve as a neuroimmune substrate for
stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun
21:47–59, 2007 [PubMed]
Frasure-Smith N, Lesperance F, Julien P: Major depression is associated with lower omega-3 fatty
acid levels in patients with recent acute coronary syndromes. Biol Psychiatry 55:891–896, 2004
[PubMed]
Gatti S, Bartfai T: Induction of tumor necrosis factor-alpha mRNA in the brain after peripheral
endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res
624:291–294, 1993 [PubMed]
Glaser R, Kiecolt-Glaser JK, Bonneau RH, et al: Stress-induced modulation of the immune response
to recombinant hepatitis B vaccine. Psychosom Med 54:22–29, 1992 [PubMed]
Goebel MU, Mills PJ, Irwin MR, et al: Interleukin-6 and tumor necrosis factor-alpha production after
acute psychological stress, exercise, and infused isoproterenol: differential effects and pathways.
Psychosom Med 62:591–598, 2000 [PubMed]
Goldstein R, Bowen DL, Fauci AS: Adrenal corticosteroids, in Inflammation: Basic Principles and
Clinical Correlates. Edited by Gallin JI, Goldstein IM, Snyderman R. New York, Raven, 1992, pp
1061–1082
Guarini S, Altavilla D, Cainazzo MM, et al: Efferent vagal fibre stimulation blunts nuclear
factor-kappaB activation and protects against hypovolemic hemorrhagic shock. CirculationPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
20 of 27
10/05/2009 15:52
107:1189–1194, 2003 [PubMed]
Gupta S, Aggarwal S, See D, et al: Cytokine production by adherent and non-adherent mononuclear
cells in chronic fatigue syndrome. J Psychiatr Res 31:149–156, 1997 [PubMed]
Hasler G, Drevets WC, Manji HK, et al: Discovering endophenotypes for major depression.
Neuropsychopharmacology 29:1765–1781, 2004 [PubMed]
Heim C, Owens MJ, Plotsky PM, et al: The role of early adverse life events in the etiology of
depression and posttraumatic stress disorder. Focus on corticotropin-releasing factor. Ann N Y Acad
Sci 821:194–207, 1997 [PubMed]
Herbert TB, Cohen S: Depression and immunity: a meta-analytic review. Psychol Bull 113:472–486,
1993 [PubMed]
Hickie I, Lloyd A: Are cytokines associated with neuropsychiatric syndromes in humans? Int J
Immunopharmacol 17: 677–683, 1995 [PubMed]
Hickie I, Hickie C, Lloyd A, et al: Impaired in vivo immune responses in patients with melancholia.
Br J Psychiatry 162:651–657, 1993 [PubMed]
Hohagen F, Timmer J, Weyerbrock A, et al: Cytokine production during sleep and wakefulness and
its relationship to cortisol in healthy humans. Neuropsychobiology 28:9–16, 1993 [PubMed]
Holsboer F: The corticosteroid hypothesis of depression. Neuropsychopharmacology 23:477–501,
2000 [PubMed]
Honda M, Orii F, Ayabe T, et al: Expression of glucocorticoid receptor beta in lymphocytes of
patients with glucocorticoid-resistant ulcerative colitis. Gastroenterology 118:859–866, 2000
[PubMed]
Huston JM, Ochani M, Rosas-Ballina M, et al: Splenectomy inactivates the cholinergic
antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med
203:1623–1628, 2006 [PubMed]
Ignatowski TA, Spengler RN: Tumor necrosis factor-alpha: presynaptic sensitivity is modified after
antidepressant drug administration. Brain Res 665:293–299, 1994 [PubMed]
Irwin M, Hauger RL, Brown M, et al: CRF activates autonomic nervous system and reduces natural
killer cytotoxicity. Am J Physiol 255 (5 pt 2):R744–R747, 1988
Irwin M, McClintick J, Costlow C, et al: Partial night sleep deprivation reduces natural killer and
cellular immune responses in humans. FASEB J 10:643–653, 1996 [PubMed]
Irwin M, Costlow C, Williams H, et al: Cellular immunity to varicella-zoster virus in patients with
major depression. J Infect Dis 178 (suppl 1):S104–S108, 1998
Johnson JD, O’Connor KA, Watkins LR, et al: The role of IL-1beta in stress-induced sensitization of
proinflammatory cytokine and corticosterone responses. Neuroscience 127:569–577, 2004
[PubMed]
Johnson JD, Campisi J, Sharkey CM, et al: Catecholamines mediate stress-induced increases in
peripheral and central inflammatory cytokines. Neuroscience 135:1295–1307, 2005 [PubMed]
Karalis K, Muglia LJ, Bae D, et al: CRH and the immune system. J Neuroimmunol 72:131–136, 1997
[PubMed]
Katugampola RP, Lewis VJ, Finlay AY: The Dermatology Life Quality Index: assessing the efficacy of
biological therapies for psoriasis. Br J Dermatol 156:945–950, 2007 [PubMed]
Kenis G, Maes M: Effects of antidepressants on the production of cytokines. Int J
Neuropsychopharmacol 5:401–412, 2002 [PubMed]
Kent S, Bluthe RM, Kelley KW, et al: Sickness behavior as a new target for drug development.Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
21 of 27
10/05/2009 15:52
Trends Pharmacol Sci 13:24–28, 1992 [PubMed]
Kiecolt-Glaser JK, Marucha PT, Malarkey WB, et al: Slowing of wound healing by psychological
stress (comments). Lancet 346:1194–1196, 1995 [PubMed]
Kim YK, Na KS, Shin KH, et al: Cytokine imbalance in the pathophysiology of major depressive
disorder. Prog Neuropsychopharmacol Biol Psychiatry 31:1044–1053, 2007 [PubMed]
Kohm AP, Sanders VM: Norepinephrine: a messenger from the brain to the immune system.
Immunol Today 21:539–542, 2000 [PubMed]
Kris-Etherton PM, Harris WS, Appel LJ: Fish consumption, fish oil, omega-3 fatty acids, and
cardiovascular disease. Arterioscler Thromb Vasc Biol 23:e20–e30, 2003
Labeur MS, Arzt E, Wiegers GJ, et al: Long-term intracerebroventricular corticotropin-releasing
hormone administration induces distinct changes in rat splenocyte activation and cytokine
expression. Endocrinology 136:2678–2688, 1995 [PubMed]
Lacosta S, Merali Z, Anisman H: Central monoamine activity following acute and repeated systemic
interleukin-2 administration. Neuroimmunomodulation 8:83–90, 2000 [PubMed]
Lanquillon S, Krieg JC, Bening-Abu-Shach U, et al: Cytokine production and treatment response in
major depressive disorder. Neuropsychopharmacology 22:370–379, 2000 [PubMed]
Laye S, Parnet P, Goujon E, et al: Peripheral administration of lipopolysaccharide induces the
expression of cytokine transcripts in the brain and pituitary of mice. Brain Res Mol Brain Res
27:157–162, 1994 [PubMed]
Leaf A, Kang JX, Xiao YF, et al: Clinical prevention of sudden cardiac death by n-3 polyunsaturated
fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Circulation
107:2646–2652, 2003 [PubMed]
Ledeboer A, Jekich BM, Sloane EM, et al: Intrathecal interleukin-10 gene therapy attenuates
paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root
ganglia in rats. Brain Behav Immun 21:686–698, 2007 [PubMed]
Leserman J, Jackson ED, Petitto JM, et al: Progression to AIDS: the effects of stress, depressive
symptoms, and social support. Psychosom Med 61:397–406, 1999 [PubMed]
Lesperance F, Frasure-Smith N, Theroux P, et al: The association between major depression and
levels of soluble intercellular adhesion molecule 1, interleukin-6, and C-reactive protein in patients
with recent acute coronary syndromes. Am J Psychiatry 161:271–277, 2004 [Full Text] [PubMed]
Leu SJ, Singh VK: Stimulation of interleukin-6 production by corticotropin-releasing factor. Cell
Immunol 143:220–227, 1992 [PubMed]
Leu SJ, Shiah IS, Yatham LN, et al: Immune-inflammatory markers in patients with seasonal
affective disorder: effects of light therapy. J Affect Disord 63:27–34, 2001 [PubMed]
Leung DY: Atopic dermatitis: immunobiology and treatment with immune modulators. Clin Exp
Immunol 107 (suppl 1):25–30, 1997
Linthorst AC, Flachskamm C, Holsboer F, et al: Intraperitoneal administration of bacterial endotoxin
enhances noradrenergic neurotransmission in the rat preoptic area: relationship with body
temperature and hypothalamic-pituitary-adrenocortical axis activity. Eur J Neurosci 7:2418–2430,
1995a
Linthorst AC, Flachskamm C, Muller-Preuss P, et al: Effect of bacterial endotoxin and interleukin-1
beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone
levels: an in vivo microdialysis study. J Neurosci 15:2920–2934, 1995b
Maes M: Major depression and activation of the inflammatory response system. Adv Exp Med Biol
461:25–46, 1999 [PubMed]Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
22 of 27
10/05/2009 15:52
Maes M, Song C, Lin A, et al: The effects of psychological stress on humans: increased production of
pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine
10:313–318, 1998 [PubMed]
Maes M, Christophe A, Delanghe J, et al: Lowered omega 3 polyunsaturated fatty acids in serum
phospholipids and cholesteryl esters of depressed patients. Psychiatry Res 85:275–291, 1999a
Maes M, Libbrecht I, Van Hunsel F, et al: The immune-inflammatory pathophysiology of
fibromyalgia: increased serum soluble gp130, the common signal transducer protein of various
neurotrophic cytokines. Psychoneuroendocrinology 24:371–383, 1999b
Maes M, Lin AH, Delmeire L, et al: Elevated serum interleukin-6 (IL-6) and IL-6 receptor
concentrations in posttraumatic stress disorder following accidental man-made traumatic events.
Biol Psychiatry 45:833–839, 1999c
Maes M, Song C, Lin AH, et al: Negative immunoregulatory effects of antidepressants: inhibition of
interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology
20:370–379, 1999d
Maier SF, Watkins LR: Cytokines for psychologists: implications of bidirectional immune-to-brain
communication for understanding behavior, mood, and cognition. Psychol Rev 105:83–107, 1998
[PubMed]
Maier SF, Goehler LE, Fleshner M, et al: The role of the vagus nerve in cytokine-to-brain
communication. Ann N Y Acad Sci 840:289–300, 1998 [PubMed]
Marchand F, Perretti M, McMahon SB: Role of the immune system in chronic pain. Nature Reviews
Neuroscience 6:521–532, 2005 [PubMed]
Mathias SD, Colwell HH, Miller DP, et al: Health-related quality of life and functional status of
patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther
22:128–139, 2000 [PubMed]
McEwen BS, Biron CA, Brunson KW, et al: The role of adrenocorticoids as modulators of immune
function in health and disease: neural, endocrine and immune interactions. Brain Res Brain Res Rev
23:79–133, 1997 [PubMed]
McKay LI, Cidlowski JA: Molecular control of immune/inflammatory responses: interactions
between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocrinol Rev
20:435–459, 1999 [PubMed]
Miller AH: Neuroendocrine and immune system interactions in stress and depression. Psychiatr Clin
North Am 21:443–463, 1998 [PubMed]
Miller AH, Spencer RL, Hassett J, et al: Effects of selective type I and II adrenal steroid agonists on
immune cell distribution. Endocrinology 135:1934–1944, 1994 [PubMed]
Miller AH, Pearce B, Pariante C: Immune system and central nervous system interactions, in Kaplan
and Sadock’s Comprehensive Textbook of Psychiatry, Vol 1. Philadelphia, PA, Lippincott Williams &
Wilkins, 2000, pp 113–133
Miller RJ, Sutherland AG, Hutchison JD, et al: C-reactive protein and interleukin 6 receptor in
post-traumatic stress disorder: a pilot study. Cytokine 13:253–255, 2001 [PubMed]
Milligan ED, Nguyen KT, Deak T, et al: The long term acute phase-like responses that follow acute
stressor exposure are blocked by alpha-melanocyte stimulating hormone. Brain Res 810:48–58,
1998 [PubMed]
Milligan ED, Sloane EM, Langer SJ, et al: Repeated intrathecal injections of plasmid DNA encoding
interleukin-10 produce prolonged reversal of neuropathic pain. Pain 126:294–308, 2006 [PubMed]
Mioni C, Bazzani C, Giuliani D, et al: Activation of an efferent cholinergic pathway produces strongPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
23 of 27
10/05/2009 15:52
protection against myocardial ischemia/reperfusion injury in rats. Crit Care Med 33:2621–2628,
2005 [PubMed]
Moalem G, Tracey DJ: Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev
51:240–264, 2006 [PubMed]
Moore P, Landolt HP, Seifritz E, et al: Clinical and physiological consequences of rapid tryptophan
depletion (comment). Neuropsychopharmacology 23:601–622, 2000 [PubMed]
Moraska A, Campisi J, Nguyen KT, et al: Elevated IL-1beta contributes to antibody suppression
produced by stress. J Appl Physiol 93:207–215, 2002 [PubMed]
Müller N, Riedel M, Scheppach C, et al: Beneficial antipsychotic effects of celecoxib add-on therapy
compared to risperidone alone in schizophrenia. Am J Psychiatry 159:1029–1034, 2002 [PubMed]
Müller N, Schwarz MJ, Dehning S, et al: The cyclooxygenase-2 inhibitor celecoxib has therapeutic
effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot
study to reboxetine. Mol Psychiatry 11:680–684, 2006 [PubMed]
Munck A: Glucocorticoid physiology and homeostasis in relation to anti-inflammatory actions, in
Anti-Inflammatory Steroid Action: Basic and Clinical Aspects. New York, Academic Press, 1989, pp
30–47
Musselman DL, Nemeroff CB: Depression and endocrine disorders: focus on the thyroid and adrenal
system. Br J Psychiatry 30 (suppl):123–128, 1996
Musselman DL, Lawson DH, Gumnick JF, et al: Paroxetine for the prevention of depression induced
by high-dose interferon alfa (comments). N Engl J Med 344:961–966, 2001a
Musselman DL, Miller AH, Porter MR, et al: Higher than normal plasma interleukin-6 concentrations
in cancer patients with depression: preliminary findings. Am J Psychiatry 158:1252–1257, 2001b
Nesse RM, Williams GC: Why We Get Sick. New York, Times Books, 1994
Nishioka T, Kurokawa H, Takao T, et al: Differential changes of corticotropin releasing hormone
(CRH) concentrations in plasma and synovial fluids of patients with rheumatoid arthritis (RA).
Endocr J 43:241–247, 1996 [PubMed]
Norbiato G, Bevilacqua M, Vago T, et al: Glucocorticoid resistance and the immune function in the
immunodeficiency syndrome. Ann N Y Acad Sci 840:835–847, 1998 [PubMed]
Norris JG, Benveniste EN: Interleukin-6 production by astrocytes: induction by the neurotransmitter
norepinephrine. J Neuroimmunol 45:137–145, 1993 [PubMed]
Oakley RH, Sar M, Cidlowski JA: The human glucocorticoid receptor beta isoform. Expression,
biochemical properties, and putative function. J Biol Chem 271:9550–9559, 1996 [PubMed]
Opp MR: Cytokines and sleep. Sleep Med Rev 9:355–364, 2005 [PubMed]
Owens MJ, Nemeroff CB: Physiology and pharmacology of corticotropin-releasing factor. Pharmacol
Rev 43:425–473, 1991 [PubMed]
Owens MJ, Nemeroff CB: The role of corticotropin-releasing factor in the pathophysiology of
affective and anxiety disorders: laboratory and clinical studies. Ciba Found Symp 172:296–308;
discussion 308–216, 1993
Owens MJ, Nemeroff CB: The serotonin transporter and depression. Depress Anxiety 8 (suppl
1):5–12, 1998
Pace TW, Mletzko TC, Alagbe O, et al: Increased stress-induced inflammatory responses in male
patients with major depression and increased early life stress. Am J Psychiatry 163:1630–1633,
2006 [Full Text] [PubMed]
Pace TW, Hu F, Miller AH: Cytokine-effects on glucocorticoid receptor function: relevance toPrint: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
24 of 27
10/05/2009 15:52
glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav
Immun 21:9–19, 2007 [PubMed]
Paez Pereda M, Sauer J, Perez Castro C, et al: Corticotropin-releasing hormone differentially
modulates the interleukin-1 system according to the level of monocyte activation by endotoxin.
Endocrinology 136:5504–5510, 1995
Paik IH, Toh KY, Lee C, et al: Psychological stress may induce increased humoral and decreased
cellular immunity. Behav Med 26:139–141, 2000 [PubMed]
Papanicolaou DA: Euthyroid sick syndrome and the role of cytokines. Rev Endocr Metab Disord
1:43–48, 2000 [PubMed]
Papanicolaou DA, Wilder RL, Manolagas SC, et al: The pathophysiologic roles of interleukin-6 in
human disease. Ann Intern Med 128:127–137, 1998 [PubMed]
Pariante CM, Miller AH: Glucocorticoid receptors in major depression: relevance to pathophysiology
and treatment. Biol Psychiatry 49:391–404, 2001 [PubMed]
Pariante CM, Nemeroff CB, Miller AH: Glucocorticoid receptors in depression. Isr J Med Sci
31:705–712, 1995 [PubMed]
Pariante CM, Pearce BD, Pisell TL, et al: The proinflammatory cytokine, interleukin-1alpha, reduces
glucocorticoid receptor translocation and function. Endocrinology 140:4359–4366, 1999 [PubMed]
Parker G, Gibson NA, Brotchie H, et al: Omega-3 fatty acids and mood disorders. Am J Psychiatry
163:969–978, 2006 [Full Text] [PubMed]
Pavlov VA, Tracey KJ: The cholinergic anti-inflammatory pathway. Brain Behav Immun 19:493–499,
2005 [PubMed]
Pearce BD: Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms. Mol
Psychiatry 6:634–646, 2001 [PubMed]
Peet M, Horrobin DF: A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients
with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen
Psychiatry 59:913–919, 2002 [PubMed]
Persoons P, Vermeire S, Demyttenaere K, et al: The impact of major depressive disorder on the
short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment Pharmacol
Ther 22:101–110, 2005 [PubMed]
Plotkin SR, Banks WA, Kastin AJ: Comparison of saturable transport and extracellular pathways in
the passage of interleukin-1 alpha across the blood-brain barrier. J Neuroimmunol 67:41–47, 1996
[PubMed]
Quan N, Stern EL, Whiteside MB, et al: Induction of pro-inflammatory cytokine mRNAs in the brain
after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J Neuroimmunol
93:72–80, 1999 [PubMed]
Rabin BS: Stress, Immune Function, and Health: The Connection. New York, Wiley, 1999
Raison CL, Miller AH: The neuroimmunology of stress and depression. Semin Clin Neuropsychiatry
6:277–294, 2001 [PubMed]
Raison CL, Miller AH: Depression in cancer: new developments regarding diagnosis and treatment.
Biol Psychiatry 54:283–294, 2003a
Raison CL, Miller AH: 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, 2003b
Raison CL, Nemeroff CB: Cancer and depression: prevalence, diagnosis, and treatment. Home Health
Care Consultant 7:34–41, 2000Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
25 of 27
10/05/2009 15:52
Raison CL, Gumnick JF, Miller AH: Neuroendocrine-immune interactions: implications for health and
behavior, in Hormones, Brain and Behavior, Vol 5. San Diego, CA, Academic Press, 2002, pp
209–261
Raison CL, Capuron L, Miller AH: Cytokines sing the blues: inflammation and the pathogenesis of
depression. Trends Immunol 27:24–31, 2006 [PubMed]
Rassnick S, Sved AF, Rabin BS: Locus coeruleus stimulation by corticotropin-releasing hormone
suppresses in vitro cellular immune responses. J Neurosci 14:6033–6040, 1994 [PubMed]
Ressler KJ, Nemeroff CB: Role of norepinephrine in the pathophysiology and treatment of mood
disorders. Biol Psychiatry 46:1219–1233, 1999 [PubMed]
Reynolds JL, Ignatowski TA, Sud R, et al: Brain-derived tumor necrosis factor-alpha and its
involvement in noradrenergic neuron functioning involved in the mechanism of action of an
antidepressant. J Pharmacol Exp Ther 310:1216–1225, 2004 [PubMed]
Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N
Engl J Med 353:1711–1723, 2005 [PubMed]
Ridker PM, Hennekens CH, Buring JE, et al: C-reactive protein and other markers of inflammation in
the prediction of cardiovascular disease in women. N Engl J Med 342:836–843, 2000a
Ridker PM, Rifai N, Stampfer MJ, et al: Plasma concentration of interleukin-6 and the risk of future
myocardial infarction among apparently healthy men. Circulation 101:1767–1772, 2000b
Rivest S, Lacroix S, Vallieres L, et al: How the blood talks to the brain parenchyma and the
paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli.
Proc Soc Exp Biol Med 223:22–38, 2000 [PubMed]
Roitt I, Bostoff J, Male D: Immunology. New York, CV Mosby, 1998
Rothermundt M, Arolt V, Bayer TA: Review of immunological and immunopathological findings in
schizophrenia. Brain Behav Immun 15:319–339, 2001 [PubMed]
Ruzek MC, Pearce BD, Miller AH, et al: Endogenous glucocorticoids protect against
cytokine-mediated lethality during viral infection. J Immunol 162:3527–3533, 1999 [PubMed]
Sanders V, Kavelaars A: Adrenergic regulation of immunity, in Psychoneuroimmunology, 4th
Edition. Edited by Ader R. Burlington, MA, Elsevier Academic Press, 2007, pp 63–84
Schaffler A, Scholmerich J, Salzberger B: Adipose tissue as an immunological organ: toll-like
receptors, C1q/TNFs and CTRPs. Trends Immunol 28:393–399, 2007 [PubMed]
Schleifer SJ, Keller SE, Bond RN, et al: Major depressive disorder and immunity. Role of age, sex,
severity, and hospitalization. Arch Gen Psychiatry 46:81–87, 1989 [PubMed]
Schobitz B, De Kloet ER, Holsboer F: Gene expression and function of interleukin 1, interleukin 6
and tumor necrosis factor in the brain. Prog Neurobiol 44:397–432, 1994 [PubMed]
Schulte HM, Bamberger CM, Elsen H, et al: Systemic interleukin-1 alpha and interleukin-2 secretion
in response to acute stress and to corticotropin-releasing hormone in humans. Eur J Clin Invest
24:773–777, 1994 [PubMed]
Shahidi H, Vottero A, Stratakis CA, et al: Imbalanced expression of the glucocorticoid receptor
isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic
lymphocytic leukemia. Biochem Biophys Res Commun 254:559–565, 1999 [PubMed]
Shen Y, Connor TJ, Nolan Y, et al: Differential effect of chronic antidepressant treatments on
lipopolysaccharide-induced depressive-like behavioural symptoms in the rat. Life Sci
65:1773–1786, 1999 [PubMed]
Shuto H, Kataoka Y, Horikawa T, et al: Repeated interferon-alpha administration inhibits
dopaminergic neural activity in the mouse brain. Brain Res 747:348–351, 1997 [PubMed]Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
26 of 27
10/05/2009 15:52
Silverman MN, Miller AH, Biron CA, et al: Characterization of an interleukin-6- and
adrenocorticotropin-dependent, immune-to-adrenal pathway during viral infection [see comment].
Endocrinology 145:3580–3589, 2004 [PubMed]
Silverman MN, Pearce BD, Biron CA, et al: Immune modulation of the
hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Vir Immunol 18:41–78, 2005
[PubMed]
Silverman MN, Macdougall MG, Hu F, et al: Endogenous glucocorticoids protect against
TNF-alpha-induced increases in anxiety-like behavior in virally infected mice. Mol Psychiatry
12:408–417, 2007 [PubMed]
Simen BB, Duman CH, Simen AA, et al: TNFalpha signaling in depression and anxiety: behavioral
consequences of individual receptor targeting. Biol Psychiatry 59:775–785, 2006 [PubMed]
Simopoulos AP: Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr
21:495–505, 2002 [PubMed]
Sluzewska A: Indicators of immune activation in depressed patients. Adv Exp Med Biol 461:59–73,
1999 [PubMed]
Snider LA, Swedo SE: Pediatric obsessive-compulsive disorder. JAMA 284:3104–3106, 2000
[PubMed]
Sousa AR, Lane SJ, Cidlowski JA, et al: Glucocorticoid resistance in asthma is associated with
elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol
105:943–950, 2000 [PubMed]
Spivak B, Shohat B, Mester R, et al: Elevated levels of serum interleukin-1 beta in combat-related
posttraumatic stress disorder. Biol Psychiatry 42:345–348, 1997 [PubMed]
Stenzel-Poore MP, Heinrichs SC, Rivest S, et al: Overproduction of corticotropin-releasing factor in
transgenic mice: a genetic model of anxiogenic behavior. J Neurosci 14(5, pt 1):2579–2584, 1994
Steptoe A, Willemsen G, Owen N, et al: Acute mental stress elicits delayed increases in circulating
inflammatory cytokine levels (comments). Clin Sci 101:185–192, 2001 [PubMed]
Sternberg EM, Hill JM, Chrousos GP, et al: Inflammatory mediator-induced
hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall
arthritis-susceptible Lewis rats. Proc Natl Acad Sci U S A 86:2374–2378, 1989 [PubMed]
Stoll AL, Severus WE, Freeman MP, et al: Omega 3 fatty acids in bipolar disorder: a preliminary
double-blind, placebo-controlled trial (comments). Arch Gen Psychiatry 56:407–412, 1999
[PubMed]
Tanskanen A, Hibbeln JR, Tuomilehto J, et al: Fish consumption and depressive symptoms in the
general population in Finland. Psychiatr Serv 52:529–531, 2001 [Full Text] [PubMed]
Tiemeier H, van Tuijl HR, Hofman A, et al: Plasma fatty acid composition and depression are
associated in the elderly: the Rotterdam Study. Am J Clin Nutr 78:40–46, 2003 [PubMed]
Tracey KJ: The inflammatory reflex. Nature 420:853–859, 2002 [PubMed]
Trask P, Esper P, Riba M, et al: Psychiatric side effects of interferon therapy: prevalence, proposed
mechanisms, and future directions. J Clin Oncol 18:2316–2326, 2000 [PubMed]
Tyring S, Gottlieb A, Papp K, et al: Etanercept and clinical outcomes, fatigue, and depression in
psoriasis: double-blind placebo-controlled randomised phase III trial [see comment]. Lancet
367:29–35, 2006 [PubMed]
van Westerloo DJ, Giebelen IA, Florquin S, et al: The vagus nerve and nicotinic receptors modulate
experimental pancreatitis severity in mice. Gastroenterology 130:1822–1830, 2006
Veith RC, Lewis N, Linares OA, et al: Sympathetic nervous system activity in major depression.Print: Chapter 9. Brain-Immune System Interactions: Relevance to the … http://www.psychiatryonline.com/popup.aspx?aID=417362&print=yes…
27 of 27
10/05/2009 15:52
Basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch Gen Psychiatry
51:411–422, 1994 [PubMed]
Wang H, Liao H, Ochani M, et al: Cholinergic agonists inhibit HMGB1 release and improve survival in
experimental sepsis. Nat Med 10:1216–1221, 2004 [PubMed]
Wang X, Wu H, Miller AH: Interleukin 1alpha (IL-1alpha) induced activation of p38
mitogen-activated kinase inhibits glucocorticoid receptor function. Mol Psychiatry 9:65–75, 2004
[PubMed]
Webster JC, Oakley RH, Jewell CM, et al: Proinflammatory cytokines regulate human glucocorticoid
receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a
mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci U S A 98:6865–6870,
2001 [PubMed]
Wong ML, Kling MA, Munson PJ, et al: Pronounced and sustained central hypernoradrenergic
function in major depression with melancholic features: relation to hypercortisolism and
corticotropin-releasing hormone. Proc Natl Acad Sci U S A 97:325–330, 2000 [PubMed]
Yirmiya R, Pollak Y, Barak O, et al: Effects of antidepressant drugs on the behavioral and
physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacology
24:531–544, 2001 [PubMed]
Zhu CB, Carneiro AM, Dostmann WR, et al: p38 MAPK activation elevates serotonin transport
activity via a trafficking-independent, protein phosphatase 2A-dependent process. J Biol Chem
280:15649–15658, 2005 [PubMed]
Zhu CB, Blakely RD, Hewlett WA: The proinflammatory cytokines interleukin-1beta and tumor
necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 31:2121–2131,
2006 [PubMed]
Zobel AW, Nickel T, Kunzel HE, et al: Effects of the high-affinity corticotropin-releasing hormone
receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res
34:171–181, 2000 [PubMed]
Zorrilla E, Luborsky L, McKay JR, et al: The relationship of depression and stressors to
immunological assays: a meta-analytic review. Brain Behav Immun 15:199–226, 2001 [PubMed]
Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Brain-Immune Interactions
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Understanding the Brain-Immune Interface
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The Role of Cytokines in Neuroinflammation
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Neuroimmune Communication Pathways
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Quiz on Brain-Immune Connection Basics
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Historical Perspectives on Brain-Immune Research
Mapping the Immune System in Neuropsychiatric Disorders
Mechanisms of Brain-Immune Communication
Innovative Therapeutic Approaches in Neuropsychiatry
Future Directions in Brain-Immune Research
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