Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_205_библиотеки_им_акад_М_И_Перельмана
.pdf
https://t.me/med1917
CHAPTER 7
https://t.me/med1917
Role
of the Immune System
in Mood Disorders
Marisa Toups, M.D.
Charles B. Nemeroff, M.D., Ph.D.
Although significant advances in treating mood disorders have been
made using drugs and other therapies that target the brain, significant progress
remains to be made in developing personalized treatments. Increasing understanding of the complexity of mental disorders has expanded the view of them as diseases
of “neurotransmitters” to diseases of brain circuits and to, in some cases, diseases that
involve the entire living system (Akil et al. 2018). Psychoneuroimmunology is a grow
ing field that takes a systems approach to understanding behavior after modulating
the function of the immune system and, therefore, its interconnection with the ner
vous system (Ader et al. 1995). Over the last few decades, our understanding of the
role of immune function in mood disorders has grown, and psychoneuroimmunol
ogy is likely to make major contributions to clinical practice in the next few decades.
In this chapter, we outline the essentials of immune function, describe the current evi
dence supporting a role for immune function dysregulation in mood disorders, and
explore emerging evidence that interventions that impact the immune system may be
useful in treatment.
-
-
-
-
Thanks to Alyssa Marron for assistance with the figure and to Margaret Balfour for editorial
input.
133
134 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
The Immune System
The immune system recognizes and protects self-cells while eliminating invading
pathogens, infected cells, or cancerous cells (Nathan 2002). This is achieved via four
main functions that occur as part of an immune response to infection or injury: 1) rec
ognition, 2) response, 3) resolution, and 4) memory. The immune system is divided
into innate and adaptive arms, which work together in all four functions. The cells of
the innate immune system, which include macrophages, dendritic cells, and natural
killer cells, among others, monitor the blood and tissue and respond to any insults
through production of cytokines or presentation of antigens to the adaptive immune
system (Akira et al. 2006). Cells of the adaptive immune system, B lymphocytes and
T lymphocytes, primarily reside in lymph nodes and related tissue, although some
also circulate in the blood. The adaptive response temporally lags behind the innate,
especially for new infections, and also activates various strategies to eliminate the insults. In addition, it is responsible for the memory function of the immune system and
thus is critical for maintaining lifelong immunity to infections (Iwasaki and Medzhi
tov 2015). Figure 7–1 shows the major classes of immune cells and their roles in responding to infection.
A major component of the immune response is the generation of cytokines and
chemokines, which attract immune cells to infected or damaged tissue, activate other
immune cells, amplifying the response to the insult, direct the development of immune cells, activate the differentiation of T and B cells, participate in the immune
memory formation, and promote the clearance of the insult. Several of these cyto
kines, particularly those driving the immediate short-term response to infection, appear to be dysregulated in depression. These include interleukin-6 (IL-6), IL-1β, and
tumor necrosis factor-α (TNF-α
ble 7–1 summarizes the most studied cytokines, their main functions, and associations with depression and bipolar disorder.
), as well as the anti-inflammatory cytokine IL-10. Ta-
-
-
-
Immune Responses Inside the Central Nervous System
The CNS has specialized immune cells (Norris and Kipnis 2019). Because the bloodbrain barrier (BBB) restricts the infiltration of peripheral immune cells, the brain possesses microglia—specialized macrophage-like cells that perform innate immune
functions and account for up to 10% of brain cells (Kim and de Vellis 2005). Microglial
ancestor cells enter the brain during embryonic development and sustain their population throughout life. In health, they perform “housekeeping,” such as assisting
with synaptic plasticity by eliminating synapses. However, they can be activated into
distinct states, such as promoting inflammation or enhancing tissue repair, which
may be associated with neurodegenerative and neuropsychiatric disease (Yirmiya
2000). Under pathological circumstances—CNS infection, severe systemic infection
(e.g., sepsis), or profound stress—when the BBB is compromised, circulating cells
from the periphery enter the brain parenchyma, damaging the brain (Varatharaj and
Galea 2017). Whether this process is a significant contributor to mental disorders is an
active area of study.
135 Role of the Immune System in Mood Disorders
https://t.me/med1917
FIGURE 7–1. Immune cells and their roles in the immune response.
To view this figure in color, see Plate 2 in Color Gallery in middle of book.
(1) Immune recognition: A monocyte recognizes pathogen-associated molecular patterns (PAMPs) on an in-
fected cell using a toll-like receptor (TLR). (2) Activation: Inflammatory cytokines are produced by cells at the
site of infection, and this draws other innate immune cells. (3a) Antigen presentation: A dendritic cell presents
fragments of pathogen to T cells, looking for a match. (3b) Meanwhile, innate immune cells such as natural
killer (NK) cells and neutrophils directly and indirectly attack the infected cells, inducing apoptosis or cell
death. (4a) B cells that can make antibodies effective against the pathogen mature into plasma cells for imme-
diate production and memory cells to facilitate response if the same pathogen is encountered again. Mature
lymphocytes will direct resolution of the response as it completes. (4b) Matching T cells mature into helper
T cells and cytotoxic T cells that integrate the immune response and directly attack infected cells, respectively.
+
cell= a critical subpopulation of MHC class I restricted T cells; FAS=a type II membrane protein
CD8
within the tumor necrosis family; HLA=human leukocyte antigen; IL=interleukin; MHC= major histocom
patibility complex; TCR =T cell receptor; T
response by stimulating other immune cells; T
mune response by stimulating other immune cells; TNF=tumor necrosis factor; TRAIL=TNF-related apoptosis-inducing ligand.
1 CD4+=a type of lymphocyte that helps coordinate the immune
H
2 CD4+=a type of lymphocyte that helps coordinate the im-
H
-
136 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
TABLE 7–1. Commonly studied cytokines in mental health and their main
functions, as well as mood-related findings
Cytokine Type Main function Clinical findings
IL-1β Inflammatory Coordinates/activates
inflammatory cascade
IL-2 Differentiator Promotes T cell survival Increased in MDD
IL-4 Differentiator Promotes Th2-associated Decreased in MDD
allergic responses
IL-6 Inflammatory Activates the acute phase
response
IL-10 Anti-inflammatory Inhibits the production of
proinflammatory cytokines
IFN-γ Inflammatory Responds to infection,
especially viral
TNF-α Inflammatory Plays a critical role in
multiple cellular functions:
survival, proliferation,
differentiation, and death
Other
C-reactive
protein
IFN=interferon, IL=interleukin; MDD=major depressive disorder; Th2=T helper type 2 cells; TNF=
tumor necrosis factor.
a
C-reactive protein is an acute-phase reactant, not a cytokine.
Acute phase
a
reactant
Participates in the complement
pathway activation or
promotes phagocytosis
pathogens by macrophages
Activated in MDD
Increased in MDD;
increased in mania
Increased in MDD
Decreased in MDD
Increased in MDD;
increased in mania
Increased in MDD
Communication Between the Brain
and the Immune System
The brain receives signals from the immune system in several ways. As mentioned
above, when the immune cells enter the CNS, they also produce cytokines, which can
be detected in the cerebrospinal fluid (Banks and Erickson 2010) and enhance damage. Peripherally produced and circulating cytokines may enter the CNS through
openings of the BBB, such as the circumventricular organs (Quan and Banks 2007).
Cytokine signals are also received via direct detection by nerves, particularly those of
the autonomic nervous system (Dantzer et al. 2000). The existence of a lymphatic system within the meninges of the brain has been validated and represents another potential route by which cells and circulating cytokines may reach the CNS (Sandrone et
al. 2019).
Reciprocally, the brain communicates with and modulates the immune system (Qiu
et al. 1996). Both the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic
nervous system contribute to control of immune cells (Sternberg 2006), and both are
involved in suppressing cytokine production as well as in resolving the immune response (Rosas-Ballina and Tracey 2009). The peripheral anti-inflammatory effects of
137 Role of the Immune System in Mood Disorders
https://t.me/med1917
cortisol, which is a major component of the stress response, include inhibition of the
infiltration of the immune cells around the body as well as the release of cytokines
(Dhabhar 2009; Silverman and Sternberg 2012). The catecholamines norepinephrine
and epinephrine also modulate the activity of the immune system, in particular by directly impacting immune cells.
Evidence of Immune Dysfunction
in Mood Disorders
Although it appears that a range of psychiatric illnesses may involve immune dysfunction, the most promising potential for future treatment applications exists for
mood disorders, particularly major depressive disorder (MDD). Overall, the existing
literature supports an immune dysregulation in MDD with the following character
istics: 1) mild but chronic elevations of proinflammatory cytokines, 2) chronic elevations in some anti-inflammatory cytokines, and 3) suppressed immune cell response.
Similar patterns of dysregulation of the immune system have been found in other dis
eases (e.g., diabetes, cardiovascular disease, obesity), underlying some of the potential mechanisms mediating the high rates of comorbidity between these diseases and
depression.
There are several important clinical contributors to immune dysregulation in depressed patients, including stress, particularly early in life. Additionally, at least in
some cases, a primary immune cause, such as a drug therapy or an autoimmune dis
ease, may be associated with depression development. Few data exist on the immune
response in patients with bipolar disorder. Although mania is considered to be asso
ciated with increased inflammation, there is less evidence linking bipolar depression
with immune dysfunction (Goldsmith et al. 2016).
The finding that clinically depressed subjects exhibit elevated markers of inflammation when compared with healthy subjects has been extensively replicated (Haapakoski et al. 2015). C-reactive protein (CRP) is one of the most studied inflammatory
markers in MDD because, empirically, CRP has been used as a marker of cardiovascu
lar disease risk and can be obtained from most clinical labs, making it ideal for clinicians. CRP in healthy adults is less than 1–3 mg/L. Levels greater than 3 mg/L indicate
chronic inflammation, and levels greater than 100 mg/L are associated with active se
vere bacterial infection (D’Agostino et al. 2008). In samples of patients with MDD, the
mean CRP value is elevated compared with that of healthy subjects, and depressed
patients are more likely to have levels greater than 3 mg/L. Some severely depressed
patients may have CRP levels elevated into the range associated with chronic inflammation (Raison et al. 2013).
In addition to laboratory findings, there is substantial epidemiological evidence
linking depression and immune dysfunction. Epidemiologists have noted the high
rate of medical comorbidity in depressed patients for decades, and chronic disorders
such as metabolic syndrome and cardiovascular disease carry up to a doubled risk of
depression (Anderson et al. 2001; Evans et al. 2005; Heiskanen et al. 2006). Similarly,
autoimmune disorders and severe infections increase future risk of depression by
about 50% (Benros et al. 2013). Interestingly, depression increases the longitudinal
-
-
-
-
-
-
138 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
risk of developing many of these same medical disorders, as well as cancer, over time
(Currier and Nemeroff 2014; Goldbacher et al. 2009), suggesting bidirectionality of
underlying mechanisms. One might guess that the association of depression with in
creased inflammation would protect patients with MDD from infection, but paradoxically they are at greater risk of minor infections (Cohen 1995) and may not respond
successfully to vaccines (Irwin et al. 2011). Depression is also associated with a signif
icant increase in longitudinal risk for serious infection (Andersson et al. 2016) and
with increased infection-related mortality (Davydow et al. 2016).
Clinical Contributors to Immune Dysfunction
in Depression
To realize the goal of advancing mood disorder treatment, we as researchers and clinicians need to understand the etiology of the co-occurring immune dysfunction and
identify patients for whom psychoneuroimmunology-based therapies might be ben
eficial. For example, it is not yet clear whether immune dysfunction is universal or
impacts only a subset of patients (Glassman and Miller 2007). We also lack a clear un
derstanding of the “which came first?” directionality of these associations; although
data support the conclusion that the depressed population has signs of immune dys
regulation, many of these patients may have preexisting factors that contribute to
their mood disorder.
-
-
-
-
-
Diet
In a study by Lucas et al. (2014), diet that was associated with elevated inflammatory
markers was also associated with depression symptoms, with a relative risk of ap
proximately 1.3 for the highest inflammatory quintile. Although this study was limited by the inclusion of only female subjects, these results suggest that diet increases
depression risk primarily through chronic inflammation, and that the high preva
lence of poor-quality diet and associated obesity among psychiatric patients is a likely
contributor to depression-associated inflammation.
Psychological Stress
The relationship between stress and immune response is dependent on the nature of
the stressor and the population under study (Segerstrom and Miller 2004). Occupational or interpersonal stress may be associated with an increase in inflammatory cytokines (Maes et al. 1998). Agreater inflammatory stress response is observed in individuals with higher chronic or baseline stress, and this effect may be most pronounced in
those with depression or anxiety. This increase in inflammatory markers may explain
the increased vulnerability to infection (Cohen 1995), because psychosocial stress has
been associated with a decrease in the gene expression associated with antiviral immunity (Miller et al. 2008).
Early-life stress or trauma may be the major contributor to inflammation in mood
disorders. Early-life adversity—a well-known risk factor for adult psychopathology—also substantially increases risk of metabolic and inflammatory illness in adulthood (Ehlert 2013; Su et al. 2015), including obesity and elevated CRP (Baumeister et
-
-
139 Role of the Immune System in Mood Disorders
https://t.me/med1917
al. 2016; Coelho et al. 2014). Survivors of childhood trauma have epigenetic changes
in genes regulating HPA axis function (Danese et al. 2011; Nemeroff 2016) and also
exhibit behavior changes impairing cortisol sensitivity, such as insomnia (Miller et al.
2011). There is at least some evidence that the effects of childhood and later-life
trauma on inflammation are additive (Hostinar et al. 2015; Lin et al. 2016).
Iatrogenic Inflammation
Mood episodes induced by medications impacting immune responses have been in
the scope of psychiatric practice for many years. Corticosteroids and related immu
nosuppressants cause mania in susceptible individuals upon acute administration,
and depression after prolonged exposure (Warrington and Bostwick 2006). Perhaps
the best evidence relates to interferon-α (IFN-α) therapy for hepatitis C virus infection,
melanoma, or other illness; IFN-α induces depressive symptoms in approximately
45% of the patients receiving this treatment. Exogenous immune stimulation is suffi
cient to induce sickness behavior. Amazingly, close to half may go on to develop a full
major depressive episode, including symptoms such as worthlessness and suicidal
ideation (Capuron and Miller 2004). Having a history of depression is a risk factor for
interferon-induced depression (Schlaak et al. 2012). The depressive effects of interferon therapy provided some of the first evidence that altering the immune system is
capable of causing depression.
-
-
Autoimmune and Other Illnesses
Given the overlap between medical illnesses and mood disorders, the population of
patients with an obviously immune diathesis to their disorder is important to con
sider. In particular, individuals with autoimmune disorders have extremely high
rates of comorbid MDD, reportedly as high as 40% (Benros et al. 2013). This overlap
might be attributed to the direct impact of immune activity in the brain (e.g., cytokines or immune cell infiltration [Pryce and Fontana 2017]). Patients with cancer also
often experience increased inflammation from the cancer as well as tissue-destructive
therapies (Mantovani et al. 2008) and have high rates of comorbid depression that is
associated with poor outcomes (Bortolato et al. 2017), suggesting that inflammation
is the common theme associated with the development of depression. Thus, consid
eration of the particular vulnerability of these patients may warrant measures to
screen for and treat mood symptoms in these patients.
Interventions for Inflammatory Depression
In this section, we discuss three interesting questions related to treatment of mood
disorders and immune responses. First, is there an association between antidepres
sant treatment and normalization of immune system function? Next, does restoring
immune function result in a therapeutic mood effect? And finally, can immune markers be used to select patients for specific antidepressant treatments, regardless of
whether those treatments are immune related?
Data on whether antidepressant treatment improves immune dysfunction, as as-
sessed via meta-analysis (Köhler et al. 2018), are mixed. Part of this heterogeneity is
-
-
-
140 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
likely attributable to treatment with different modalities and drugs; however, more
work needs to be done to examine this question. The latest analysis specifically failed
to find a connection between the observed decreases in IL-6, the cytokine most con
sistently elevated in MDD, and improvement in symptoms with treatment (Köhler et
al. 2018). Other therapies, such as exercise, mindfulness, and even psychotherapies
such as cognitive-behavioral therapy, have also been associated with reductions in in
flammatory markers, and thereby provide broader support for a nonspecific effect
based more on ameliorating the disease state than on mechanism of treatment (Eyre
et al. 2013; Lopresti 2017; Morgan et al. 2014).
Two major sets of data examine treating the immune dysfunction in depression
directly with cytokine-inhibiting drugs or nonsteroidal anti-inflammatory drugs
(NSAIDs). Anticytokine therapy is typically in the form of manufactured monoclonal
antibodies that target cytokines or related molecules. Most of the relevant trials include subjects treated for an autoimmune disease with comorbid depression and show
consistently positive results (Kappelmann 2018). One study in a sample of patients
with severe unipolar depression without medical comorbidity had negative results
overall, but found that the subjects with the highest levels of inflammation, as assessed with CRP level, appeared to benefit from treatment with the TNF-α antagonist
infliximab (Raison et al. 2013). A similar trial enrolling subjects with bipolar depres
sion showed no effect, perhaps because bipolar depression is less related to immune
dysfunction than is unipolar depression (McIntyre et al. 2019). It remains to be seen,
given the risks associated with these drugs and the mixed results, whether cytokine
inhibitors will find use outside of the niche of patients with comorbid inflammatory
illnesses. NSAIDs have also been studied as primary or augmentation treatments,
with mostly positive findings (O. Köhler et al. 2014). In particular, selective cyclooxygenase-2 (COX-2) inhibitor drugs have been found to be effective treatments for
MDD. Unfortunately, other studies have found no effect, and chronic NSAID use is
not without risks (Eyre et al. 2015).
Finally, we consider whether there is any recommendation for matching currently
accepted therapies with patients with the goal of improving the remission rate by iden
tifying patients who may benefit from targeted therapy (e.g., patients with medical comorbidity or patients with a history of childhood trauma). A few secondary analyses
of large studies found evidence that inflammation, as assessed with CRP level, is associated with a poorer response to treatment with selective serotonin reuptake inhibitors
(Hedayati et al. 2017; O’Brien et al. 2007) compared with dopamine reuptake inhibitors
(Jha et al. 2017; Uher et al. 2014). However, more research on the topic is needed. Some
trials also suggest that exercise may be especially beneficial for depressed patients with
elevated cytokines (Greer and Trivedi 2009; Rethorst et al. 2013), although researchers
do not yet understand which types of exercise are most effective in reducing inflammation, and therefore depression symptoms (Eyre and Baune 2014).
-
-
-
-
Conclusion
As of this writing, we can conclude that mood disorders involve abnormal immune
responses. Major depressive disorder shows substantial associations with poorer outcomes when combined with medical illness involving inflammation. Nevertheless,
141 Role of the Immune System in Mood Disorders
https://t.me/med1917
work remains to better understand how the multiple clinical phases of bipolar disorders relate to immune and medical outcomes. Given the rapid increase in the understanding of immune responses and technological advances allowing the development
of new assays and treatments, it is likely that psychiatrists will soon see major new
therapies applying the knowledge base of psychoneuroimmunology to treatment of
mood disorders in the clinic.
References
Ader R, Cohen N, Felten D: Psychoneuroimmunology: interactions between the nervous sys-
tem and the immune system. Lancet 345(8942):99–103, 1995 7815892
Akil H, Gordon J, Hen R, et al: Treatment resistant depression: a multi-scale, systems biology
approach. Neurosci Biobehav Rev 84:272–288, 2018 28859997
Akira S, Uematsu S, Takeuchi O: Pathogen recognition and innate immunity. Cell 124(4):783–
801, 2006 16497588
Anderson RJ, Freedland KE, Clouse RE, Lustman PJ: The prevalence of comorbid depression
in adults with diabetes: a meta-analysis. Diabetes Care 24(6):1069–1078, 2001 11375373
Andersson NW, Goodwin RD, Okkels N, et al: Depression and the risk of severe infections:
prospective analyses on a nationwide representative sample. Int J Epidemiol 45(1):131–
139, 2016 26708840
Banks WA, Erickson MA: The blood-brain barrier and immune function and dysfunction. Neu-
robiol Dis 37(1):26–32, 2010 19664708
Baumeister D, Akhtar R, Ciufolini S, et al: Childhood trauma and adulthood inflammation: a
meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factoralpha. Mol Psychiatry 21(5):642–649, 2016 26033244
Benros ME, Waltoft BL, Nordentoft M, et al: Autoimmune diseases and severe infections as risk
factors for mood disorders: a nationwide study. JAMA Psychiatry 70(8):812–820, 2013
23760347
Bortolato B, Hyphantis TN, Valpione S, et al: Depression in cancer: the many biobehavioral
pathways driving tumor progression. Cancer Treat Rev 52:58–70, 2017 27894012
Capuron L, Miller AH: Cytokines and psychopathology: lessons from interferon-alpha. Biol
Psychiatry 56(11):819–824, 2004 15576057
Coelho R, Viola TW, Walss-Bass C, et al: Childhood maltreatment and inflammatory markers:
a systematic review. Acta Psychiatr Scand 129(3):180–192, 2014 24205846
Cohen S: Psychological stress and susceptibility to upper respiratory infections. Am J Respir
Crit Care Med 152(4 Pt 2):S53–S58, 1995 7551414
Currier MB, Nemeroff CB: Depression as a risk factor for cancer: from pathophysiological
advances to treatment implications. Annu Rev Med 65:203–221, 2014 24215332
D’Agostino RB Sr, Vasan RS, Pencina MJ, et al: General cardiovascular risk profile for use in pri-
mary care: the Framingham Heart Study. Circulation 117(6):743–753, 2008 18212285
Danese A, Caspi A, Williams B, et al: Biological embedding of stress through inflammation pro-
cesses in childhood. Mol Psychiatry 16(3):244–246, 2011 20157309
Dantzer R, Konsman JP, Bluthé RM, Kelley KW: Neural and humoral pathways of communi-
cation from the immune system to the brain: parallel or convergent? Auton Neurosci 85(1–
3):60–65, 2000 11189027
Davydow DS, Ribe AR, Pedersen HS, et al: The association of unipolar depression with thirty-
day mortality after hospitalization for infection: a population-based cohort study in Denmark. J Psychosom Res 89:32–38, 2016 27663108
Dhabhar FS: A hassle a day may keep the pathogens away: the fight-or-flight stress response
and the augmentation of immune function. Integr Comp Biol 49(3):215–236, 2009 21665815
Ehlert U: Enduring psychobiological effects of childhood adversity. Psychoneuroendocrinol-
ogy 38(9):1850–1857, 2013 23850228
Соседние файлы в папке Библиотека им академика М.И. Перельмана