Maes et al. BMC Medicine 2012, 10:66
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REVIEW

Open Access

Depression and sickness behavior are Janus-faced
responses to shared inflammatory pathways
Michael Maes1*, Michael Berk2,3,4,5, Lisa Goehler6, Cai Song7,8, George Anderson9, Piotr Gałecki10 and
Brian Leonard11

Abstract
It is of considerable translational importance whether
depression is a form or a consequence of sickness
behavior. Sickness behavior is a behavioral complex
induced by infections and immune trauma andmediated by pro-inflammatory cytokines. It is anadaptive response that enhances recovery byconserving energy to combat acute inflammation.
There are considerable phenomenological similarities
between sickness behavior and depression, forexample, behavioral inhibition, anorexia and weight
loss, and melancholic (anhedonia), physio-somatic(fatigue, hyperalgesia, malaise), anxiety andneurocognitive symptoms. In clinical depression,
however, a transition occurs to sensitization of
immuno-inflammatory pathways, progressive damageby oxidative and nitrosative stress to lipids, proteins,and DNA, and autoimmune responses directedagainst self-epitopes. The latter mechanisms are thesubstrate of a neuroprogressive process, whereby
multiple depressive episodes cause neural tissue
damage and consequent functional and cognitive
sequelae. Thus, shared immuno-inflammatory
pathways underpin the physiology of sickness
behavior and the pathophysiology of clinicaldepression explaining their partially overlapping
phenomenology. Inflammation may provoke a Janusfaced response with a good, acute side, generating
protective inflammation through sickness behavior
and a bad, chronic side, for example, clinicaldepression, a lifelong disorder with positive feedback
loops between (neuro)inflammation and (neuro)
degenerative processes following less well defined
triggers.
* Correspondence: dr.michaelmaes@hotmail.com
1
Maes Clinics @ TRIA, Piyavate Hospital, 998 Rimklongsamsen Road, Bangkok
10310, Thailand
Full list of author information is available at the end of the article

Keywords: depression, sickness behavior, inflammation, oxidative stress, cytokines

Introduction
The first inkling that there are phenomenological similarities between clinical depression and sickness behavior andthat both conditions may share common pathways, that is,
activation of the inflammatory responses system (IRS) was
published in 1993 [1,2]. Sickness behavior is a behavioral
complex that is typically induced by acute infections andtissue injury in many mammalian species. The characteristic behavioral pattern consists of malaise, hyperalgesia,
pyrexia, listlessness and disinterest in social interactions
with the environment, lethargy, behavioral inhibition,
reduction of locomotor activity, exploration and grooming,
reduction of reproductive performance, anhedonia, somnolence and sleepiness, anorexia and weight loss, failure toconcentrate, and anxiety. There is evidence that sickness
behavior is mediated through the effects of pro-inflammatory cytokines (PICs), such as IL-1, TNFa and IL-6 [3-10].
In this context, there is abundant evidence that clinicaldepression is an immuno-inflammatory disorder characterized by among other things increased levels of PICs andacute phase proteins, including C-reactive protein andhaptoglobin [11-20].
Characteristic symptoms of major depression include
anorexia, weight loss, fatigue, lethargy, sleep disorders,
hyperalgesia, reduction of locomotor activity, and failure
to concentrate (American Psychiatric Association).
Moreover, ‘vegetative symptoms’ of depression, such as
anorexia, weight loss, and psychomotor retardation, aresignificantly associated with inflammatory markers inclinical depression, such as increased levels of plasma
haptoglobin, an acute phase protein, synthesis of which isinduced by the three abovementioned PICs [1,2].
Thus, it may be concluded that there are striking
behavioral and inflammatory similarities between bothsickness behavior and clinical depression [1,2,11].

© 2012 Maes et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

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Therefore, some authors regard clinical depression as aform of sickness behavior and/or as a consequence ofthe sickness behavioral response [9]. Figure 1 shows thetheory - principally derived from inflammatory translational models - that inflammatory triggers cause IRS
activation and induce the production of PICs, which inturn may provoke sickness behavior and depression,
thus explaining the phenomenological overlap between
these conditions.
The main aims of this paper are to delineate: a) thesymptomatic and behavioral similarities and dissimilarities between both clinical depression and sickness behavior; b) the staging of depression versus the course of
sickness behavior; c) the shared immuno-inflammatory
pathways that both underpin clinical depression andsickness behavior and may discriminate them; and d)
the etiologic factors in both conditions.
The nature of sickness behavior

Inflammatory inducers, for example acute viral and bacterial infections and inflammatory trauma, are detectedby sentinels (for example, receptors on the innate
immune system) and activate inflammatory mediators,
for example, PICs which target the immune cells in the
inflamed tissues [21]. Adaptive inflammatory responses
are terminated once the triggers are eliminated anddamaged tissues are repaired, a phenomenon known as
resolution of inflammation. As we will explain in thissection PIC-induced sickness behavior plays an important role in the resolution of inflammation andincreased energy demands during inflammation.
Sickness and energy consumption

Combating pathogen threats consumes large amounts ofenergy and, therefore, rations available energy [22]. PIC
signals, for example, TNFa signals, modulate the balance between this increased energy demand and energy

Depression

Acute triggers
Acute infections
Tissue injury

Inflammation
PICs

Basic depressive
Melancholic
Physio-somatic
Anxiety and
Neurocognitive
symptoms

Sicknessbehaviour

Figure 1 Inflammation causes sickness and depression. This
Figure shows the theory that acute triggers cause inflammation andincreased production of pro-inflammatory cytokines (PICs), which is
associated with the onset of sickness behavior and clinicaldepression.

supply and control food intake, energy expenditure andsubstrate utilization [23,24]. PICs play a key role in thishighly increased energy request characterized by a negative energy balance (increased lipolysis, loss of tissue
proteins and lowered muscle protein synthesis, gluconeogenesis) and decreased voluntary energy utilization[22]. The central nervous system (CNS) receives neuraland humoral signals about the peripheral inflammatory
response through PIC-induced activation of afferent
vagal signals, effects of TNFa at the sensory nuclei ofthe solitary tract, and all three PICs entering the brain
though different pathways [22,25]. These PICs, in turn,will shut off energy-consuming processes, such as locomotor, neurocognitive and reproductive activity. Thus,
metabolic energy is withdrawn from the brain and someperipheral organs and redirected to counteract theadverse effects of the invading pathogens. The energy
saved by this process contributes to pyrexia and to theenhancement of the inflammatory state of immune cells[22]. Many of the sickness behavior symptoms, such asanergia, malaise, somnolence, psychomotor retardation,
cognitive deficits and loss of libido serve to limit motor,
sexual and brain activity and thereby direct metabolicenergy to combating the primary infection [4,7,22,26].
Immune responses are highly calorie dependent andincrease resting energy expenditure, while sickness behavior responses, for example, motor inhibition, may conserve critical energy [27].
Sickness behavior and pyrexia

Mild to moderate pyrexia (in contrast to high fever) is apositive adaptive response as it strengthens the hostdefenses and resistance to infection, for example, byenhancing the phagocytosis and mobility of polymorphonuclear leukocytes and killing of bacteria and preventing
viral replication [28-30]. In addition, PICs and cytokines,
such as IFNs are more active during fever [31]. The relative balance of pyrogenic IL-1 and non-pyrogenic IL-18,
and their endogenous inhibitory factors in different CNS
sites, may contribute to the presence and degree of pyrexia [32]. In the past, fevers were even induced inpatients to combat infections.
Sickness behavior and anorexia and weight loss

Inflammation-induced anorexia is directly proportional tothe magnitude of the insult and is also inversely related tobody weight prior to the insult [33]. It is suggested thatanorexia may limit the intake of iron, which otherwise
would activate bacterial production [34]. Iron is one of thenutrients employed by bacteria for bacterial growth. This
reasoning is, however, highly speculative as only less than
1% of dietary iron is absorbed and iron status changes
slowly over time. A more plausible adaptive function isthat anorexia through calorie restriction attenuates

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different intracellular signaling pathways leading to inflammation and even sickness behavior [35,36]. Thus, a twoweek calorie restriction period significantly reduces
inflammatory pathways, including IL-6 [37]. Calorierestriction results in a dose-dependent suppression of lipopolysaccharide (LPS)-induced sickness behavior by inducing an anti-inflammatory state [36]. Motor inhibition andanorexia can lead to lean body mass loss, increased protein
catabolism and loss of body protein and fat mass, which
together may explain inflammation-induced weight loss
and eventually cachexia. In the short-term, weight reduction, but not the composition of the diet, attenuates the
inflammatory response, for example, by lowering inflammatory PICs, such as IL-6 and TNF [38-40] and increasingplasma levels of adiponectin, an adipose-derived antiinflammatory protein [41].
Figure 2 shows the different functions of acute inflammation-induced sickness behavior. Thus, sickness behavior
is a short-term response to acute inflammatory triggers
and is an adaptive motivational state induced to cope withthese triggers and the consequent negative energy balance[4,7]. This homeostatic adaptive behavioral response isconserved across species through evolution and occurs ina predictable form cross-culturally [26].
Symptomatic/behavioral similarities and dissimilarities
between depression and sickness behavior

The Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR, American Psychiatric Association),

Energyredirection

Immune cells--Acute Triggers
Acute Infection
Tissue injury---

sentinels---

one of the most commonly used diagnostic systems forpsychiatric disorders, considers that the diagnosis ofclinical depression can be made when at least five out ofnine basic symptoms sare present for at least two weeks.
Table 1 lists these nine basic symptoms and also threepartially overlapping symptom dimensions that may
superimpose on these basic symptoms, that is: 1) melancholic; 2) anxiety; and 3) physio-somatic dimensions[15]. It should be stressed that multivariate statisticalanalyses (pattern recognition methods) have confirmed
and validated the basic symptoms of clinical depression
and also the three symptom dimensions [42-44]. These
three dimensions delineate specific depressive subgroups, for example, depression with melancholic, anxiety or physio-somatic features, which were externallyvalidated by biomarkers.
Table 1 compares the symptoms of clinical depression
with the characteristics of sickness behavior. Basic
symptoms/behaviors of clinical depression are also
observed in sickness behavior, for example, anorexia,
weight loss, reduction of locomotor activity and exploration, fatigue, sleepiness, and failure to concentrate.
Moreover, symptoms belonging to the three dimensions,for example, melancholia (a failure to react to pleasurable stimuli, and excessive psychomotor retardation andweight loss) anxiety, and physio-somatic symptoms(malaise and hyperalgesia) also occur during sickness
behavior. An apparent difference between depression
and sickness behavior is pyrexia. There are, however,EnergystorageBrain
Muscles, etc
Negative energy balance
Loss body massProtein catabolism
Lipolysis
Loss of protein
Lower muscle mass, etc

PICs ---+++

Sickness behaviour
Listlessness
Lethargy
Reduced locomotor
activity
Behavioural inhibition
Anhedonia
Anxiety
Sleepiness
Somnolence
Disinterest
MalaiseHyperalgesia
Failure to concentrate
Anorexia
Weight loss
Pyrexia

Figure 2 This figure shows the functions of acute inflammation-induced sickness behavior: a) energy saving by protecting the organism
from the energy consuming effects of inflammation (through somnolence, lethargy, sleepiness, hyperalgesia, reduction of motor activity,
exploration and grooming, cognitive deficits, loss of libido, anhedonia, disinterest in social interactions with the environment, and anxiety); b)
anti-inflammatory effects (through anorexia, weight loss); and c) pathogen-directed effects (through pyrexia).

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Table 1 Characteristics of depression and sickness behavior.
Clinical depression

Sickness behavior

Basic
symptoms

Depressed mood most of the day
Decreased interest or pleasure in almost all activities
Anorexia, and/or significant weight loss or weight gain
Insomnia or hypersomnia
Psychomotor agitation or psychomotor retardation
Fatigue or loss of energy
Decreased ability to think or concentrate–
Disinterest in social interactions
Anorexia and weight loss; no weight gain
Sleepiness
Reduced locomotor activity; no agitation
Lethargy
Failure to concentrate

Existential
symptoms

Feelings of worthlessness or guilt
Suicidal ideation or behavior––

Melancholic
dimension

A distinct quality of depressed mood (anhedonia)
Non-reactivity
Diurnal variation
Early morning awakening
Psychomotor retardation
Excessive weight loss

Reduced intake of sweetened milk (anhedonia)
Behavioral inhibition––
Reduction of locomotor activity and exploration
Important weight loss

Anxietydimension

Tension; physiological behavior; respiratory symptoms; genitourinary symptoms; autonomic symptoms; anxious behavior atinterview (general)
Flu-like malaise; aches and pain; muscle tension (in some of thepatients)

Anxiety

Physiosomatic
dimension

Malaise and hyperalgesia (key symptoms of sickness)

Pyrexia

Slightly increased body temperature

Pyrexia

Onset
CourseInsiduous
Waxing and waning or relapsing-remitting
Chronic
Sensitization of episodes
Seasonal variation(Hypo)manic episodes

Acute onset
Acute adaptive response, maximal 19 to 43 days
May be prolonged, but then is maladaptive–––

Pathways(Sub)chronic inflammation with increased PICs
CMI activation
Sensitization of inflammatory and CMI pathways
Activation TRYCAT pathway
O&NS
Damage by O&NS
Autoimmunity
Neuroprogression

Acute inflammation with increased PICs
Activated–
Maybe activated TRYCAT pathway
Unknown but probably yes–––

Triggers

Multiple, not well defined
Psychosocial stressors, medical inflammatory illness,
neuroinflammatory disorders, inflammatory conditions

Acute, highly defined
Acute pathogens and tissue injury

Episodes tend to become autonomous from trigger

Is always a response to a defined trigger

GeneralInflammation-related chronic progressive disorder

PICs’ Janusface

Bad ‘chronic’ side: a chronic disorder with positive feedback loops
between (neuro)inflammation and (neuro)degenerative processes

Inflammation-induced adaptive behavioral response that isconserved through evolution
Good ‘acute’ side: supports inflammation, redirects energy to
immune cells, conserves energy and prevents negative energybalance, helps eradicating the trigger, and has anti-inflammatory
effects

CMI, cell-mediated immune; O&NS, oxidative and nitrosative stress; PICs, pro-inflammatory cytokines; TRYCAT, tryptophan catabolites.

some reports that major depressed patients haveincreased body temperature as compared to normal
volunteers, that is 98.38 ± 0.61 degrees F versus 98.13 ±0.59 degrees F, respectively (mean ± SD) (that is, 36.88°
C versus 36.74°C [45]. Increased body temperature inclinical depression is also shown by Szuba et al. [46].
However, there is by no means conclusive evidence ofsignificant pyrexia in patients with clinical depression.
Obvious differences are suicidal ideation, feelings of
guilt and worthlessness, symptoms indicating a

distinctive existential state of depression [26]. In thiscontext, it is important to note that Charlton proposed
the malaise theory of depression, that is, malaise, thekey symptom of sickness behavior, should be considered
the core ‘emotion’ of depression. Indeed, a flu-likemalaise or the subjective feeling of infection together
with other physio-somatic symptoms is an important
symptom dimension in clinical depression [44]. The
malaise theory regards lowered mood and the more distinctive existential state of depression as a product ofMaes et al. BMC Medicine 2012, 10:66
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malaise. Thus, humans who suffer from sickness behavior and do not know they are ill, may interpret theirlack of energy and neurocognitive disorders as a personal failure, causing feelings of guilt and unworthiness[26]. By inference, this theory considers depression notprimary as an affective disorder but as a somatic disorder related to sickness behavior. Nevertheless, multivariate statistical analyses show that only some depressed
patients suffer from physio-somatic symptoms, including
malaise [44]. These findings contrast with the view thatmalaise is a core emotion of depression.
Staging of depression versus the course of sickness
behavior

Although some patients may suffer from one depressive
episode only, longitudinal studies performed within thelast two decades have shown that clinical depression istypically an episodic or lifelong disease [47-49]. Although
depression was classically considered to be a self-limiting
disorder with a short duration (six to nine months), thecourse of depression varies considerably. It may take theform of prolonged episodes (chronic depression), anddepressive episodes may frequently return (recurrent
depression). Moreover, up to 15% of depressed patients
may develop treatment resistance, defined as a failure to
respond to at least two adequate antidepressant trials[50]. A subgroup of depressed patients additionally sufferfrom hypomanic or manic episodes (bipolar depression),including abnormally elevated mood, energy and cognition; or from a mixed state with depressive and (hypo)
manic symptoms occurring together. It should be underscored that the brain is one of the most metabolically
active tissues, and energy and mood are intertwined.
Depression is linked to reductions in brain energy generation and mania to increased energy expenditure [51],while sickness behavior is a behavioral response, whichconserves energy.
Both unipolar and bipolar depression have characteristics of a progressive illness: they both follow stages, often
commencing with mild or non-specific symptoms, progressing to prodromal features of subthreshold symptoms,
then an acute episode, recurrence or a chronic form of
persistent, unremitting illness [16,17,48]. An earlier onset
of depression and increased length and number of episodes are associated with increased vulnerability to further
relapses and a less favorable outcome [16,17,52]. This progressive course is associated with a functional deterioration, including neurocognitive decline [53,54]. This‘waxing and waning’ pattern is similarly characteristic ofautoimmune, progressive or degenerative disorders thatcombine an insidious onset with recurrent episodes or achronic course and increased risk for functional deficits[11]. Moreover, there is evidence that sensitization offers amodel for episode recurrence [55]. Sensitization indicates

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that repeated exposure to stressors, either psychological ororganic, causes time-dependent, progressive increases insusceptibility to re-exposure to any of these stressors[56,57]. McEwen’s allostatic load model has similarly been
adapted to describe this progressive pattern [58]. Moreover, a seasonal variation is often found in unipolar andbipolar depression and depressive subgroups, including
postpartum depression, with, for example, peak occurrences in spring [59,60]. There is also a seasonal variationin severity of depression and depressive symptoms, including suicide [61].
In contrast, sickness behavior is an acute, short-term
state most often with an acute onset that is biologicallyappropriate to combat acute infections/trauma and thus
enhances recovery. Evidently, (hypo)manic symptoms, theprogressive deterioration over time, and seasonal variation
are not characteristics of sickness behavior. Sickness behavior may be prolonged or inappropriately activated. Such a
prolonged sickness behavior complex is likely to be dysfunctional [26] as is the case in more chronic infectionsand (auto)immune disorders. Motor and activity deficits
are typically associated with sickness behavior [62,63] andform part of the fatigue - depression - sleep disorder cluster occurring during acute and chronic illnesses including
heart disease, rheumatoid arthritis, and cancer [64]. In
some individuals these symptoms can persist years after
hospitalization, for example, post ICU and post-administration of radioactive substances. The question arises as towhether this condition should be regarded as sickness
behavior given it is no longer beneficial? The following
sections will address this question.
Pathways underpinning clinical depression and sickness
behavior
Inflammation and cell-mediated immunity

Studies in humans and rodents have defined PICs as central mediators of sickness behavior [5,6,65-67]. Inflammatory triggers induce ‘neuraxes’, that is, ascending neuralpathways, which convey information about metabolic, gastro-intestinal and cardiovascular challenges to brain
regions that mediate stress-related behaviors [68,69]. For
example, infection and immune activation activate bottom-up, inflammatory pathways, mediated by PICs, fromthe periphery to the dorsal vagal complex, and ventrolateral medulla of the caudal medulla [9,70-72]. These
inflammatory challenges to internal bodily functions aretranslated into the brain via viscerosensory pathways that
subsequently drive sickness behavior, and depressive- andanxiety-like behaviors [72]. Moreover, PICs are activelytransported to the brain by endothelial cell transporters or
may diffuse through blood-brain-barrier deficient areas[25,72]. This may explain why systemic inflammation provokes neuroinflammation and microglial activation. For
example, administration of LPS, a component of theMaes et al. BMC Medicine 2012, 10:66
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bacterial wall of gram negative bacteria, causes neuroinflammation and microglial activation, characterized byincreased levels of TNFa, which may remain elevated formonths and are associated with the onset of sickness
behavior [8]. Moreover, the same pathways may activate
brain regions, for example, the bed nucleus of the stria terminalis, that mediate threat-related information and infection-induced anxiety [71,73-75]. Studies investigating themechanisms of these behavioral deficits in acute illness
models have shown that peripheral inflammation leads toactivation of a ‘danger pathway’ that originates in the caudal brainstem and signals the presence of physiologicalstressors to regulatory brain regions including the
hypothalamus. Activation of this danger pathway leads tothe suppression of hypothalamic arousal systems, notably
the tuberomammillary histaminergic system, associatedwith behavioral activity [68]. When activation of the danger pathway is prevented, motor aspects of sickness behavior are absent following acute inflammatory challenge[69]. Thus, reduction in behavior associated with sickness
is concomitant with an active inhibition of arousal systems[76]. The danger pathway also provides input to otherbrainstem areas involved in the regulation of arousal
including the serotonergic dorsal raphe nucleus [68,69],
and in this way may serve as a link between peripheral
inflammation and brain functions regulating and/or influenced by alterations in arousal states.
As reviewed previously, clinical depression and sickness
behavior share the involvement of key pathways, the predominant one being the role of inflammation [15]. In
clinical depression there is evidence of a chronic, lowgrade inflammatory process and cell-mediated immune(CMI) activation characterized by a T helper (Th1)-like
response with activation of IFNg-related pathways[77,78]. Recent meta-analyses and recent publications
have confirmed increased levels of PICs in humandepression particularly IL-6, TNFa, and IL-1, and CMI
activation, evidenced by higher levels of neopterin andsoluble IL-2 receptors (sIL-2Rs) [18-20,79,80]. Increased
neopterin is a marker of increased IFNg mediated macrophage activation. In humans, IFNa-based immunotherapy induces physio-somatic and depressive symptoms inmany patients with hepatitis C virus. The onset of
depressive symptoms during IFNa-based immunotherapy
is strongly associated with induction of the cytokine network, including elevations in monocytic cytokines, Th-1like and Th-2-like cytokines [18,81,82].
Elevated PICs and CMI cytokines are capable of producing depressive symptoms and administration of cytokines
provides a robust experimental model of the acute phaseof depression. Studies in the rodent [15] provide strong
evidence that PICs, for example IL-1, IL-6, and TNFa, andCMI cytokines, for example IL-2 and IFNg, all at around
50 μg/kg, may induce: a) sickness behavior; b) depressive-

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like symptoms (including loss of motivated behavior,
reduction of social investigation, anorexia, weight loss,
decreased spontaneous locomotor activity, increased locomotion, memory impairment, impaired spatial memory,and enhancement of the amnesic effect of scopolamine);c) melancholic symptoms (including anhedonia as indicated by reduced preference for a solution of sucrose or
chocolate milk in comparison to water, and changes in thecircadian clock through effects at the suprachiasmatic
nucleus); d) anxiety (including anxiogenic effects in theelevated plus maze and elevation of conditioned fear
memory); and e) physio-somatic symptoms (including fatigue, hyperalgesia, and autonomic symptoms). Administration of LPS elicits not only sickness behavior but also
depressive- (suppression of social interaction and activity
in the open-field test, food consumption and body weight,
memory dysfunction), anxiety-like and physio-somatic
behaviors [15]. Cytokines such as IL-1 not only havepotent primary signaling effects, but also modulate manyneurotransmitters intimately involved in mood regulationsuch as serotonin and noradrenaline [83]. Recently, theinflammatory processes were linked with the neurocircuitry hypothesis of depression [84]. Thus, PICs modulate
cortical-striatal-limbic circuits, which process rewardbased and affective information and are responsible forcore depressive symptoms [84].
Certainly, it is difficult to determine whether the depressogenic and anxiogenic effects of LPS and other inflammatory triggers are genuine or related to sickness behavior[85]. Since cytokine- and LPS-based models are accompanied by depressive-like and sickness behaviors it was often
difficult to delineate which of these models are characteristic for acute depressive-like behaviors or for sickness
behavior. Nevertheless, some groups have apparently separated initial sickness behavior from depressive-like behaviors. Dissociation between LPS-induced depressive-likebehaviors and sickness behavior could be established by
testing mice at different time points following administration of LPS [86]. Lacosta et al. (1999) [87] showed that systemic administration of IL-2 to mice induces reductions in
exploration and impaired performance in the Morris
water-maze that are not related to sickness behavior.
Administration of intracerebroventricular (icv) IL-1b
induces a sickness behavioral response (as indicated by
reduced locomotor activity, lethargy, and reduced bodyweight) and a stress- or anxiety-like response [88].
Activation of the IRS is controlled at different levels
whereby regulatory mechanisms specifically target selected
control points, such as the production of pro-inflammatory mediators or the effects of mediators on the target tissues [21,89]. This regulation of the IRS response is anadapted compartmentalized regulatory response characterized by reflex inhibition that tends to silence an overzealous IRS [90]. Examples of inflammatory reflex inhibition

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are inflammation-induced increases in IL-10, a negative
immunoregulatory cytokine, and transforming growth factor (TGF)b, an antiproliferative factor [21]. PIC-inducedchanges in neural pathways also participate in inhibiting
acute inflammation, for example, enhanced production of
glucocorticoids and catecholamines, and activation of cholinergic pathways [91]. For example, counter regulatory
mechanisms are initiated to limit an infectious (sepsis) andnon-infectious systemic inflammatory response syndrome[90,92,93]. This counter anti-inflammatory response syndrome is an adaptive response of the immune status thatdampens an overzealous inflammatory response caused bypathogens or immune trauma [90,92,93].
The existence of comparable counter regulatory processes, in particular reflex inhibition, has been described inclinical depression [11,78]: increased synthesis of the IL-1
receptor antagonist (IL-1RA), which inhibits the functionof IL-1; PIC-induced activation of the cortisol-axis and theconsequent immunosuppressive activities of glucocorticoids; increased IL-6 production, which is protective by
increasing the production of IL-10, IL-1RA and glucocorticoids; increased IL-2R levels which induce a state of IL-2
starvation by binding their ligand and limiting the amountof IL-2 needed for immune cell proliferation; increased
production of some acute phase proteins, for example, haptoglobin, which act as immunosuppressive factors;
increased prostaglandin production, which may suppress
lymphoproliferative responses; and lowered plasma tryptophan levels (see next section). These counter anti-inflammatory response syndrome mechanisms may explain why
the immune-inflammatory response in clinical depressionis accompanied by signs of immunosuppression, such as
decreased ex vivo natural killer cell activity and mitogeninduced lymphoproliferative disorders [11]. In analogy withthe term counter anti-inflammatory response syndrome,
which is typically coined as a counter-regulatory response
to sepsis/systemic inflammatory response syndrome, wewould propose to label this compensatory reflex system as‘compensatory (anti)inflammatory reflex system’ (CIRS).
Sickness behavior supports the protective inflammatory response (helps to eradicate the trigger and redirects energy to inflammatory cells), protects against
possible detrimental effects of inflammation (for example, negative energy balance), while at the same time
acting as an anti-inflammatory reflex (anti-inflammatory
effects of calorie restriction and weight loss). Therefore,
sickness behavior itself should be regarded as a CIRS
response to acute inflammation. Thus, while clinicaldepression is accompanied by a CIRS that downregulates the immuno-inflammatory response, sickness behavior is part of a CIRS.
The TRYCAT (tryptophan catabolite) pathway

Recently, a new pathway associated with inflammation
has been established in some individuals with

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depression, that is, activation of the tryptophan catabolite (TRYCAT) pathway [94-97]. The first and rate-limiting enzyme of this pathway is indoleamine 2,3dioxygenase (IDO; EC 1.13.11.52) [98]. IDO is activatedby IFNg and by PICs, such as IL-1 and TNFa, thereby
inducing the catabolism of tryptophan leading to tryptophan depletion and increased synthesis of TRYCATs,
for example, kynurenine, kynurenic acid, xanthurenic
acid, and quinolinic acid. IDO is expressed in manyorgans, for example, kidney, lung, spleen, and duodenum, immune cells, and the brain, for example, astroglia
and microglia [99,100]. Lowered plasma tryptophan frequently occurs in clinical depression and is strongly
associated with biomarkers of inflammation (acutephase reactants, increased cytokine levels) and CMI activation (increased serum neopterin and sIL-2Rs) [94-96].
During IFNa-based immunotherapy the onset of depressive symptoms is strongly associated with IDO activation, as assessed by means of the kynurenine/tryptophan
ratio [101]. Likewise, in the postnatal period lowered
tryptophan and increased IDO activity are related toanxiety and depressive symptoms [102]. Acute tryptophan depletion causes a robust increase in depressive
symptoms in vulnerable individuals [103].
Recent studies have shown that IDO activation may
separate sickness behavior and depressive-like behaviors
in the rodent [104]. Thus, in Wild type (WT) mice,inoculation with bacille Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, elicits IDO activation and consequent elevations in PICs and CMIcytokines, such as IFNg, IL-1b and TNFa [104]. Inoculation with BCG caused an initial acute episode of sickness
behavior that was followed by a chronic state of depressive-like symptoms starting one week after BCG administration. Sickness behavior was equally induced in WT
and IFNgR(-/-) mice, whereas IFNg and TNFa together
are necessary to cause IDO activation in microglia andconsequent depressive-like behaviors. Moreover, IDOdeficient mice are resistant to the depressogenic effects
of BCG, while they show a normal inflammatory
response following BCG administration [104].
These TRYCAT data obtained in animal experiments
are, however, difficult to extrapolate to clinical depression, because the clinical results are controversial. Thus,
initial research showed no changes in urinary excretionof TRYCATs, such as xanthurenic acid and kynurenine,
after tryptophan loading in depressed patients [105-108].
Nevertheless, higher xanthurenic excretion rates wererelated to anxiety and a lowered availability of plasma
tryptophan [105,108]. The latter findings show that a‘TRYCAT shunt’ through activation of IDO lowered
plasma tryptophan in individuals with depression. In a
recent study [109], lower levels of kynurenic acid andconsequently a relatively increased kynurenine/kynurenicMaes et al. BMC Medicine 2012, 10:66
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acid ratio were observed in depression. This ratio might
be important for the pathophysiology of depression as
kynurenine and some of its catabolites, for example, quinolinic acid, are depressogenic, anxiogenic, excitotoxic
and neurotoxic, whereas kynurenic acid is neuroprotective [96]. One study shows increased TRYCATs inadolescents with melancholic depression [110] andanother study increased quinolinic acid in microglia ofdepressed suicide victims [111]. Sublette et al. [112]detected increased plasma kynurenine levels in suicide
attempters with major depression. Recent data showsthat aberrations in the TRYCAT pathway, classically seen
as a hallmark of depression, may be more germane tosomatization, suggesting that the classically labeled psychosomatic symptoms of somatization may be more
appropriately termed physio-somatic symptoms [113].
Thus, in a study comparing depression, comorbid depression + somatization, somatization alone, and controls,
plasma tryptophan was even lower in somatization thanin depression, while the kynurenine/kynurenic acid ratio
and the kynurenine/tryptophan ratio were significantly
higher in patients with somatization than depression[113]. Plasma tryptophan was negatively, and both ratios
were positively, correlated with severity of physio-somatic
symptoms. In summary, although in acute inflammatory
states (for example, during IFNa-based immunotherapy)
IDO activation is strongly related to the onset of depressive-like behaviors, this appears not to be the case in clinical depression since only some of those individuals, thatis, those with physio-somatic symptoms or suicidal behavior, show relative increases in TRYCAT levels.
IDO activation has protective CIRS functions: IDOinduced reductions in plasma tryptophan and increased
TRYCAT formation may attenuate the primary immunoinflammatory response, for example, by attenuating T cell
activation and proliferation [11,15]. This reflex inhibition
could, therefore, be involved in spontaneous remissions ofclinical depression, consistent with the observation that
depression is sometimes a self-limiting disorder [96]. ThisCIRS mechanisms may also explain the contradictory findings on the TRYCAT pathway in acute depressive states(for example, IFNa-induced depression where there is astrong association between TRYCAT aberrations and theonset of depression) and major depression (DSM-IV-TR
criteria), where these associations are much weaker probably because lowered tryptophan and increased TRYCATs
have attenuated the initial immune-inflammatory
response. Nevertheless, increased levels of TRYCATs, forexample, quinolinic acid, in the anterior cingulate gyrus
may be detrimental and play a role in clinical depression.
Detrimental immuno-inflammatory pathways that
discriminate depression from sickness behavior

Although there is some evidence that shared immunoinflammatory pathways may underpin sickness behavior

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and clinical depression, they have divergent effects inboth conditions. Thus, the inflammatory response insickness behavior has a beneficial CIRS effect on theorganism, whereas inflammatory pathways and theirsequelae have detrimental effects in depression and inparticular in recurrent and chronic depression.
Transition to sensitization and autoimmunity

There is evidence that immuno-inflammatory responses
are sensitized by recurrent depressive episodes. Thus,
neopterin, a biomarker of CMI activation, is significantly
increased in depressed patients who have experienced
two or more depressive episodes than in patients who
suffered only one depressive episode [18,114]. Likewise,
plasma IL-1 and TNFa are significantly increased indepressed patients who suffered from three or moredepressive episodes [18]. Women with a lifetime historyof depression have increased inflammatory biomarkers,
including IL-6 and sIL-1RA, in the early puerperium ascompared to women who have never suffered fromdepression [115]. Increased C-reactive protein (CRP)
levels in depressed men predict not only severity of thecurrent depressive episode, but also recurrent depression[116]. It is known that PICs mediate central sensitization, for example, behavioral responses to maternal
separation [117,118]. This suggests that recurrent
depressive episodes amplify the pathophysiologicalresponses of depressogenic cytokines, potentially enhancing inflammation-induced behavioral responses. Since
it is known that increased numbers of episodes increase
the risk of recurrence and treatment resistance [17], thefindings suggest that sensitization of immuno-inflammatory pathways increases vulnerability to develop new
depressive episodes.
Immuno-inflammatory mechanisms may also explain
the high degree of anti-5-hydroxytryptamine (5-HT) antibody activity in clinical depression (54.1%), and in melancholia (82.9%) as compared to normal controls (5.7%)[119]. This autoimmune activity directed against 5-HT issignificantly associated with biomarkers of inflammation(increased IL-1 and TNFa) and CMI activation(increased neopterin). In this respect, administration of
pro-inflammatory and CMI-related stimuli, including
LPS, IFNg, and TNFa, reduces the survival of 5-HT neurons in the dorsal raphe nucleus, an effect that is not
related to IDO activation [120]. The autoimmune activity
directed against 5-HT is additionally associated with thenumber of previous depressive episodes, suggesting that
exposure to previous depressive episodes increases anti5-HT antibody activity, which, in turn, could confer
increased risk to develop new depressive episodes.
Moreover, increased IL-6 and TNFa and lower serum
zinc levels are associated with risk for depression andtreatment-resistant depression [121-125]. This suggeststhat the immuno-inflammatory response in clinicalMaes et al. BMC Medicine 2012, 10:66
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depression may confer increased risk towards treatment
resistance [126]. There is also evidence that immunoinflammatory processes underpin the pathophysiology
not only of unipolar and bipolar depression, but alsomania [127,128]. Acute mania is accompanied byincreased sIL-6R and sIL-2R levels, and increases inacute phase reactants [127,128], increased sCD4, sCD8,
and sIL-1R antagonist levels [129], and elevated total
immunoglobulin (Ig) G1, complement proteins C3, C6
and factor B [130]. Recently, it was argued that immunoinflammatory processes play a role in the progressive
shortening of the inter-episode interval with each recurrence when bipolar depression progresses [16,17]. All inall, the aforementioned findings suggest that sensitization(kindling) and progression of depression and bipolar disorder are, in part, caused by progressive inflammatory,
CMI and autoimmune responses.
Transition to damage by O&NS processes

As with many inflammatory conditions, clinical depression is accompanied by activation of oxidative and nitrosative stress (O&NS) pathways [131]. The latter are likely
amplified by reduced antioxidant levels, for example,
coenzyme Q10, zinc and glutathione, and by the
immuno-inflammatory responses in depression, perpetuating a vicious cycle between reduced antioxidants,
inflammation and activated O&NS pathways [131]. There
are no reports whether O&NS pathways play a role inadaptive sickness behavior. Nevertheless, these pathways
have detrimental effects in clinical depression and additionally play a role in chronic depression. There is abundant evidence that depression is characterized not only
by increased reactive oxygen and nitrogen species (ROS/
RNS), but also by O&NS damage to lipids, proteins,
DNA, and mitochondria [131]. In these processes O&NS
pathways may alter the chemical structure of membrane
fatty acids and functional proteins. When these modified
fatty acids and proteins become immunogenic, an autoimmune response may be mounted directed against these‘neoepitopes’ thereby further damaging the function or
chemical structure of these epitopes [132,133]. Many
depressed patients show increased IgM-mediated autoimmune responses directed against neoepitopes, such as
the three anchorage molecules, palmitic and myristic acidand L-farnesyl S-cysteine, as well as acetylcholine, phosphatidylinositol, oleic acid, and NO-adducts, including
NO-tryptophan and NO-tyrosine [133]. These autoimmune responses may interfere with cellular functions
including intracellular signaling, apoptosis, and cellulardifferentiation. For example, the autoimmune reactions
directed against the anchorage molecules may interferewith palmitoylation, myristoylation and farnesylation,
and, therefore, with the binding and function of hundredsof proteins to the membrane [133]. Some of these IgMmediated autoimmune responses are significantly higher

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in chronically depressed patients than in non-chronicallydepressed patients, suggesting that this O&NS damage
may increase risk to develop chronic depression for
example by activating neuroprogressive pathways[16,17,52,133]. These O&NS-related processes together
with the effects of inflammatory mediators at 5-HT neurons [120] may explain the transition from inflammation
and CMI activation to damage by O&NS and autoimmune reactions, which both may aggravate the preexisting inflammation and are involved in the process ofchronic depression.
Transition to neuroprogression

Another immuno-inflammation-related pathway, which
has detrimental effects in clinical depression and is not
germane in sickness behavior, is neuroprogression, that is
the stage related and potentially progressive process ofneurodegeneration, reduced neurogenesis and neuronalplasticity, and apoptosis [15,17,123,126,134-137]. Many,
but not all depressed individuals show features suggestiveof a neuroprogressive illness. As discussed above, people
who have a longer duration of illness and suffered from
more frequent depressive episodes have a greater risk todevelop subsequent relapses. Treatment response appears
to reduce with more recurrent mood episodes [15,17,52].
Recurrent depressive episodes are correlated withincreased cognitive disabilities, for example, decreased
memory performance which is lowered by 2% to 3% following each depressive episode [138]. Depressive episodes
are additionally associated with an increased risk ofdementia [54]. Likewise, more depressive episodes areassociated with underlying brain alterations, for example,
reductions in volume of orbitofrontal and subgenual prefrontal cortex, hippocampus, and basal ganglia [52]. The
duration of illness, for example, is negatively correlatedwith the volume of cerebral grey matter [139]. Meta-analysis showed that in patients with chronic depression (> 2years) or recurrent depression hippocampal volume is significantly decreased and that the latter is related to thenumber of episodes [140,141]. In some studies, decreased
hippocampal volumes in patients with recurrent depression are associated with neurocognitive decline [142].
Treatment resistance and the duration of illness are
related to decreased right caudate and left putamen
volume [52,143]. This effect may in part be related to adecrease in soma size of some cell types [144]. There isalso evidence that in depression the abovementioned neuroprogression is at least partially caused by inflammatory
and O&NS pathways [15,17,126]. PICs, such as IL-1 andTNFa, and CMI cytokines, for example, IFNg and IL-2,
TRYCATs, such as quinolinic acid, and damage by O&NS
to structural fatty acids, anchorage molecules, functional
proteins, DNA and mitochondria all may contribute toneuroprogression [15,17,126]. Further, both immune challenge and depression influence a constellation of brain

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regions that process viscerosensory and regulation of emotion in humans [145-147] and rodents [148]. These
regions include parts of the medial prefrontal cortex (anterior cingulate) and basal forebrain (nucleus accumbens).
Intriguingly, the CIRS seems to weaken with progressionof the illness, and this failure to dampen inflammatory
activation might play a role in the process of neuroprogression seen with multiple episodes [149].
All in all, the abovementioned findings show that clinicaldepression is accompanied by chronic inflammatory andO&NS responses and/or its sequelae, including sensitization, autoimmunity, damage by O&NS and neuroprogression. As a consequence, the inflammatory experiments
described in the previous sections do not provide mechanistic explanations as to how PICs and CMI cytokines
cause progressive clinical depression, as defined by its progressive course and progressive immuno-inflammatory
pathophysiology. These experiments nevertheless support
the view that PICs and CMI cytokines are associated withthe onset of depressive-like behaviors and the physiosomatic, melancholic, and anxiety symptomatic clusters.
However, most of these LPS- and cytokine-induced models did not separate sickness behavior from depression. In
addition, these experiments are very limited because they
select only one or two aspects of the symptom dimensionsof depression, for example, reduced intake of sweetened
milk as a model for anhedonia and thus melancholia[150]. More adequate animal models of clinical depression
should be constructed to model not only the symptomatic
dimensions, but also the typical course (self-limiting versus
waxing and waning or progressive course) and theprogressive pathophysiology (with sensitization and a transition to oxidative damage, autoimmunity and neuroprogression) of clinical depression.
Etiologic factors in depression and sickness behavior

Etiologically, sickness behavior is conceptualized as anacute phase of adaptive CIRS behavior in response toacute infections and inflammatory trauma [4,7,26]. Whenthe resolution phase, however, is not induced, for example,
when the IRS was unable to eradicate the pathogen,inflammation may persist despite the CIRS thus causing achronic inflammatory state [21]. Chronic inflammation
may result from a failure to eradicate the acute inflammatory trigger (for example, pyogenic bacteria), innately
chronic irritants (for example, fungi, sarcoidosis), or autoimmune responses [151]. Acute and chronic inflammation
are distinguished in terms of immune response patterns
and time course. The time point of transition of acuteinflammation to chronic inflammation is also related tothe time when the energy stores become empty and this isestimated to be around 19 to 43 days depending on thenature of the energy store [152]. This transition is related
to a number of inflammatory sequelae, including cachexia,
insulin resistance, anemia, osteopenia and hypertension

Page 10 of 19[152]. Sickness behavior thus plays a critical role in preventing the transition from acute to chronic inflammation
following an acute trigger by compensating for the negative energy balance, redirecting energy to the activatedimmune cells, and so on [152]. Clinical depression, on theother hand, is accompanied by chronic inflammatory processes and is associated with less well defined trigger factors, as will be explained in this section.
In many chronic disorders, including degenerative (forexample, diabetes, atherosclerosis) and neurodegenerative(for example, Parkinson’s disorder) disorders the initiating
trigger is not well defined, while the chronic state appears
to consist of positive feedback loops connecting chronic
inflammation and its pathophysiological process [21]. For
example, Parkinson’s disease (PD) is characterized by avicious cycle between microglial activation and dopaminergic neuron degeneration, caused by detrimental effectsof PICs, O&NS, and so on [25]. A similar pattern isobserved in clinical depression: a chronic inflammatory
process appears to be associated with transition to progressive autoimmune and neuroprogressive processes.
In contrast to sickness behavior, pathogens do not play amajor role in clinical depression although some authors
have attempted to make links between pathogens such as
herpes simplex type 2 and toxoplasma gondii and psychopathology [153,154]. In a previous review, we concluded
that there is no good quality evidence that acute infections
and infections with Epstein-Barr Virus (EBV) may act as
trigger factors associated with the onset of clinical depression [155]. Only some types of chronic infection are frequently associated with clinical depression, for example,
HIV infection [156] and increased translocation of gramnegative bacteria [157]. Some chronic infections, such as
Lyme’s disease can cause prominent neuropsychiatricsequelae [158,159]. Thus, while sickness behavior is anadaptive CIRS response to acute infections, only a few
chronic pathogenic conditions appear to be associatedwith the onset of clinical depression. However, it cannot
be excluded that reactivated dormant infected states andconsequent infection-induced molecular pathways may be
important in clinical depression. Viral infections of thebrain, for example, cause neurologic and psychiatric dysfunction more often than appreciated [160].
Multiple trigger factors may provoke depressive behaviors, for example, psychosocial stressors, various medical
disorders, and conditions as different as hemodialysis,
IFNa-based immunotherapy, and the postnatal period[25,65,80]. Psychosocial stressors in humans may induce
inflammatory, Th1-like and O&NS responses, including
lipid peroxidation and DNA damage, while in the rodent
different types of stressors induce peripheral and central
activation of inflammatory, O&NS and neuroprogressive
pathways [25,65,80,161]. For example, in the rodent, social
defeat stress increases the reactivity of microglia to LPS,

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suggesting a role for social stress factors in the regulationof microglia responses [162]. Therefore, it may be concluded that psycho-traumatic and psychosocial stressors
may cause depression and depressive-like behaviors
through activation of immuno-inflammatory, O&NS andneuroprogressive pathways.
Many different medical disorders and conditions, which
are associated with immuno-inflammatory and O&NS
pathways, show a high comorbidity with depression: a)
medical disorders, such as chronic obstructive pulmonary
disease (COPD), cardiovascular disorder (CVD), chronic
fatigue syndrome, obesity and the metabolic syndrome,rheumatoid arthritis (RA), systemic lupus erythematosus(SLE), inflammatory bowel disease (IBD), psoriasis, osteoporosis, and diabetes type 1 and 2; b) neurodegenerative
or neuroinflammatory disorders, such as Alzheimer’s(AD), PD and Huntington’s disease, multiple sclerosis(MS) and stroke; and c) conditions, such as hemodialysis,
IFNa-based immunotherapy, and the postnatal period[25,163]. We have argued that these disorders/conditions
are all accompanied by activation of immuno-inflammatory and O&NS pathways and therefore may cause thebasic immune/inflammatory state which may lead tocomorbid depression [25]. Likewise, the same pathways
could induce sickness behavior, which is experienced as
feeling unwell, aches and pains, fatigue, and so on. However, while sickness behavior, per definition, is an adaptive
response, comorbid depression worsens the aforementioned medical conditions [25]. Concomitant depression
lowers the quality of life and increases disability and mortality in individuals with COPD, CVD, RA, SLE, IBD, psoriasis and diabetes type 1 and 2. Comorbid depression also
contributes to lowered quality of life in individuals with
MS, PD, AD, and stroke, negatively influences recovery
from neurological defects, and predicts a higher morbidity
and mortality in individuals with those neurological disorders. These negative effects of comorbid depression may
be explained by increases in (neuro)inflammatory burden,
including TRYCAT production, damage by O&NS, transition to autoimmunity and neuroprogression, which all
together may drive the (neuro)inflammatory progressionof the abovementioned medical conditions. During IFNabased immunotherapy the incidence of depression was
highest on the 12th week of treatment, when more than
20% of patients with Hepatitis C Virus had moderate/
severe depressive symptoms [164]. Physio-somatic symptoms, including fatigue, increased in the first week of treatment, and predicted cognitive-depressive symptoms someweeks to months later [165]. Thus, IFNa-based immunotherapy is probably one of the only trigger factors ofdepression that is characterized by transition from anacute inflammatory state (accompanied by sickness behavior) to a chronic inflammatory state (accompanied bydepression).

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Another factor that discriminates sickness behavior fromdepression is that the former is a response to a specificimmune trigger, whereas the association between depressogenic triggers and depression is not always present. For
example, as depressed people suffer from recurrent
depressive episodes, it is less likely that stressful triggers
are required to manifest depression. Following more thannine previous episodes, the trigger - depression association
is muted and episodes appear autonomously, disconnectedfrom triggers [166]. Also this effect may be explained by
the knowledge that depression is a progressive disorderand that depressive episodes become sensitized [17].
The above suggests that chronic animal models suchas the chronic mild stress and olfactory bulbectomized
rat model are superior to the acute cytokine or LPSinduced models in that they: a) are less ‘contaminated’
with sickness behavior; and b) more accurately represent
the psychosocial etiology, and/or (neuro)inflammatoryand (neuro)progressive pathophysiology of clinicaldepression. Thus, the chronic mild stress model in therodent shows that psychosocial triggers may cause
depression-like behaviors in association with systemic
and central inflammation and neuroprogression including decreased neurogenesis and neuronal cell damage[65]. The chronic mild stress model also mediates someof its effects from the differential regulation of the TRYCATs in different parts of the CNS [167]. A differential
increase in quinolinic acid in the amygdala and striatum,with a trend increase in kynurenic acid in the frontal
cortex following chronic mild stress would suggest an
important role for variable TRYCAT pathway activation
in mediating the changes associated with more psychosocial type stressors. Such differential TRYCAT pathway
activation in different areas in the CNS may be relevantin differentiating sickness behaviors from clinicaldepression. Also, the olfactory bulbectomized rodent
model of depression reflects the (neuro)inflammatory
and neuroprogressive phenomena observed in clinicaldepression [66,67,168,169].
Is prolonged, exaggerated or maladaptive sickness behavior
depression?

There is recent literature describing new concepts, such as
prolonged, exaggerated and maladaptive sickness behavior[170,171]. In translational models, exaggerated inflammatory and neuro-immune responses are associated with socalled ‘prolonge’” sickness behavior, including memory
deficits. Such an exaggerated response is observed in aged
as compared to adult mice [170]. This age-dependent prolonged sickness behavior is accompanied by oxidative
damage to mitochondrial DNA (mtDNA) in microglia,
increased intracellular ROS and activation of nuclear factor kappa B [170]. Subchronic administration of IL-1b significantly impairs spatial and learning memory, which iscorrelated with dysfunction of neurotrophins and their

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receptors [172]. Furthermore, the release of neurotransmitters, including acetylcholine, was significantly lower
during memory retrieval. In hippocampal neurons, IL-1b
administration significantly induced cell apoptosis,
reduced aa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, but increased N-methyl-D-aspartate
receptor changes similar to those observed in AD [173]. It
thus seems unlikely that depression is a maladaptive syndrome that results from prolonged ‘sickness behavior’ butrather the consequence of a chronic underlying immunoinflammatory and degenerative process. These findings
also show that there was no resolution to acutely triggered
inflammation and consequently that transition towards
chronic inflammatory pathology had occurred. By inference, this condition cannot be termed ‘prolonged’ sickness
behavior, because the latter term indicates a short-term
adaptive response to inflammatory trauma. Nevertheless, avalid conclusion is that shared pathways, for example,
increased levels of PIC, explain the partially overlapping
phenomenology of sickness behavior and clinicaldepression.
There is also a new hypothesis that associates depression
as an evolutionary product of sickness behavior with protection from infection. As such depression is regarded as
an evolutionary behavioral response that helps theimmune system to fight pathogens and to avoid newpathogen exposure [26,174,175]. These hypotheses, however, did not take into account that clinical depression is
not a simple behavioral response, but a progressive disorder driven by a cascading neurobiology leading to a progressive course and pathophysiology. Moreover, acutelethargy, hyperalgesia, loss of interest, anxiety, and anhedonia are beneficial behaviors, but when chronic the same
symptoms are typically not beneficial, but pathological andmaladaptive: they may further isolate the depressed patientfrom social contacts creating a state of demotivation anddemoralization and negative anticipation of the future[26]. Chronic illness, furthermore, requires a person to use
coping and adaptive strategies to integrate the consequences of a disorder. There is a wide diversity of coping
styles and beliefs on the nature of depression, some ofwhich are adaptive while others are maladaptive [176].
Antidepressive treatments

Antidepressants have significant immunoregulatory andimmunosuppressive effects in normal volunteers and animal models. Tricyclic antidepressants (TCAs) and selective
5-HT reuptake inhibitors (SSRIs) attenuate the productionof PICs, for example, IL-1b, TNFa and IL-6, and Th1-likecytokines, including IL-2 and IFNg [177]. Most antidepressants, that is, TCAs, SSRIs, reversible inhibitors of monoamine oxidase A, 5-HT and noradrenaline reuptake
inhibitors, and atypical antidepressants (for example, tianeptine) all increase the production of IL-10, a negative

Page 12 of 19

immunoregulatory cytokine and/or lower the productionof IFNg, resulting in a decreased IFNg/IL-10 production
ratio [178]. There is also evidence that SSRIs and TCAs
inhibit the production of IL-1b, TNF-a, and IL-6 in brain
cell cultures [65]. Also, in animal models antidepressantshave antiinflammatory effects [65]. Mice challenged with alethal dose of LPS are protected by bupropion administration, which significantly reduces the production of IFNg,
TNFa and IL-1b [179]. There is also evidence that antidepressants may attenuate inflammation-induced sickness
behaviors. For example, tianeptine may reduce sickness
behaviors induced by peripheral (but not central) administration of LPS and IL-1b [180]. Treatments that target
inflammation, for example, etanercept that blocks TNFa
functions, may attenuate IL-1b-induced sickness behaviors[181].
In depressed patients, on the other hand, the in vivo
effects of antidepressants are less clear. Subchronic treatments with antidepressants do not consistently attenuate
inflammatory signs in depressed patients [182,183].
Accordingly, a recent meta-analysis showed that antidepressant subclasses other than SSRIs did not attenuate theconcentrations of pro-inflammatory cytokines [184]. Thus,
despite the well-established immunoregulatory effects ofantidepressants targeting inflammation (attenuate), Th1(downregulate) and T regulatory (upregulate) functions,clinical remission in depression is not associated with normalization of immuno-inflammatory pathways [182-184].
Thus, clinical depression appears to be accompanied by a‘resistance’ to the immunosuppressive effects of antidepressants [183]. This may suggest that the immuno-inflammatory pathways are continuously activated by processes
that cannot be blocked by antidepressants, for example, by
the autoimmune responses directed against neoantigenic
determinants [133] and increased translocation of gramnegative bacteria [157]. There is also evidence that antidepressants target O&NS (attenuate), antioxidants (increase)and neuroprogressive processes (attenuate) [183]. Despite
these effects, increased activity and sensitization of
immuno-inflammatory pathways, O&NS pathways, autoimmune responses, and neuroprogression determine inpart the staging of depression, for example, treatment
resistance and recurrence of depression [52]. Thus, thesepathways may in part explain why in many trials the clinical efficacy of antidepressants does not outperform placebo[185] and why, despite being treated with antidepressants,
depressed patients show high relapse rates [186]. Therefore, new combinatorial treatment strategies are being
developed in clinical depression with drugs that target
inflammation, Th1 activation, O&NS and lowered antioxidant levels, and/or neuroprogression, for example, statins,
acetylsalicylic acid, minocycline, zinc, N-acelyl cysteine,
curcumin, ω3 polyunsaturated fatty acids, and so on [183].

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Conclusions
Figure 3 compares sickness behavior with clinicaldepression. Sickness behavior helps to eradicate the trigger, has anti-inflammatory effects and is energy saving.
As such sickness behavior enhances recovery and should
be considered as part of a CIRS, which limits an overzealous immuno-inflammatory response to acute triggers. Cross-sectionally, there are phenomenologicalsimilarities between sickness behavior and the basic
symptoms and melancholic, physio-somatic and anxiety
symptom dimensions of clinical depression. Major differences, however, are that malaise, a core symptom ofsickness behavior, occurs in some depressed patients
only, whereas significant pyrexia is confined to sickness

behavior. Moreover, depression is often accompanied
not by anorexia and weight loss but by hyperphagia andweight gain. In most individuals, depression is a lifelong
disease with a tendency towards recurrent episodes(waxing and waning), a chronic course, seasonal variation, and occasionally (hypo)manic symptoms. Moreover, sensitization and a potentially progressive
deteriorating pattern characterize the course of depression. This contrasts with sickness behavior, which isdefined as an acute, short lasting (19 to 43 days) behavioral pattern.
Translational studies show that inflammatory pathways may account for sickness behavior as well as clinical depression and, therefore, may explain the partial

Negative
immunoregulatory

CIRS
PICs
TRYCATsCMI activation

Multiple, less well defined triggers• Psychological stressors• Stroke, AD, HD, PD, MS• CVD• COPD;• RA; SLE; IBD;
• Diabetes; Metabolic syndrome• HIV infection• Cancer• Bacterial translocation• Postpartum period• Hemodialysis• IFNĮ-immunotherapy

Acute triggers
Acute infection
Tissue injury

---

O&NS
TRANSITION TO:
Damage by O&NS
Sensitization
Autoimmunity
Neuroprogression

---

---

Insiduous onset
Waxing and waning
Chronic
Sensitization
Seasonal variation(Hypo)manic episodes
PROGRESSIVE COURSE

Clinical
Depression

PICs

Phenemenologicaloverlap

PICs

Sicknessbehaviour (CIRS)---

Acute onset
ACUTE ADAPTIVERESPONSE

Figure 3 This figure compares sickness behavior with clinical depression. Sickness behavior is energy saving, helps to eradicate the trigger,
and has anti-inflammatory effects and as such enhances recovery and is part of a compensatory (anti)-inflammatory reflex system (CIRS).
Increases in pro-inflammatory cytokines (PICs) underpin both sickness behavior and clinical depression and thus may explain the partial
phenomenological overlap. Depression, however, is a chronic disorder with a specific course and pathophysiology and the presence of a CIRS
that downregulates the primary inflammatory response. Disorders in tryptophan catabolites (TRYCATs), cell-mediated immune (CMI) activation,and oxidative and nitrosative stress (O&NS), and, in particular, their sequelae (O&NS damage, sensitization, autoimmunity and neuroprogression)
are the specific organic substrates of depression. While sickness behavior is a behavioral response to acute triggers, the onset of depression isassociated with multiple less-well defined trigger factors, for example, brain disorders, such as Alzheimer (AD), Huntington (HD), and Parkinson(PD) disorder, stroke and multiple sclerosis (MS); systemic disorders, such as cardio-vascular disorder (CVD), chronic obstructive pulmonary
disorder (COPD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disorder (IBD), diabetes, metabolic syndrome,
HIV infection, cancer, bacterial translocation; and conditions, such as postpartum period, hemodialysis, and interferon-(IFN)a based
immunotherapy.

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phenomenological overlap between both conditions.
Clinical depression is accompanied by a CIRS that
downregulates the primary immuno-inflammatory
response and by a transition from inflammation and
ROS/RNS overproduction to sensitization in inflammatory and CMI responses, progressive O&NS damage andautoimmune responses. The latter pathways appear tobe the substrate of a neuroprogressive process, whereby
multiple depressive episodes cause neural tissue damage
and its functional and cognitive sequelae. Sickness behavior is also induced by immuno-inflammatory pathways,
but in contrast to clinical depression, the sickness behavioral complex has beneficial CIRS effects enhancing
recovery from the primary trigger. When there is no
resolution of the acute inflammatory phase within 19 to
43 days, chronic inflammation may ensue causing transition to chronic inflammatory pathology. Sickness behavior plays a critical role in preventing this transition bycompensating for the negative energy balance and redirecting energy to the activated immune cells.
Whereas acute infections typically elicit sickness behavior, there is not much evidence that acute pathogens
play a major role in clinical depression. While traumatic
life events can induce an inflammatory state often leading to clinical depression, no association between psychosocial stressors and sickness behavior has been
described. Comorbid depression increases morbidity andmortality in patients with (auto)immune and (neuro)
inflammatory disorders, whereas sickness behavior,when present, would tend to dampen the inflammatory
pathways.
All in all, while sickness behavior is a beneficial CIRS
response, clinical depression is a disabling, progressive
disorder. Inflammation thus provokes a Janus-faced
response with a good ‘acute’ protective inflammatoryside, involving CIRS responses, such as sickness behavior, and a bad ‘chronic’ side, that can lead to clinicaldepression, a chronic disorder with positive feedback
loops between (neuro)inflammation and (neuro)degenerative processes following less well-defined triggers.
This Janus face also represents the transition of an
inflammation-induced adaptive behavioral response thatis conserved through evolution to an inflammationrelated chronic progressive disorder, which is increasing
in prevalence in industrialized societies [187].
List of abbreviations
AD: Alzheimer disease; BCG: bacille Calmette-Guérin; CMI: cell-mediatedimmune; COPD: chronic obstructive pulmonary disease; CRP: C-reactive
protein; CVD: cardiovascular disorder; DSM IV TR: The Diagnostic andStatistical Manual of Mental Disorders, fourth edition, text revision; IBD:
inflammatory bowel disease; IDO: indoleamine 2,3-dioxygenase; IFN:
interferon; IL-1: interleukin-1; IL-1RA: IL-1 receptor antagonist; IRS:
inflammatory responses system; LPS: lipopolysaccharide; mtDNA:
mitochondrial DNA; O&NS: oxidative and nitrosative stress; PD: Parkinson

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disease; PICs: pro-inflammatory cytokines; RA: rheumatoid arthritis; ROS/RNS:
reactive oxygen and nitrogen species; sIL-2R: soluble IL-2 receptor; SLE:
systemic lupus erythematosus; SSRIs: selective 5-HT reuptake inhibitors; TCAs:
tricyclic antidepressants; TNF: tumor necrosis factor; TGF: transforming
growth factor; Th: T helper; TRYCAT: tryptophan catabolite.
Acknowledgements
The authors would like to thank Bruce Charlton for extensive discussion of
the text.
Author details
Maes Clinics @ TRIA, Piyavate Hospital, 998 Rimklongsamsen Road, Bangkok
10310, Thailand. 2School of Medicine, Deakin University, Kitchener House,
Ryrie Street, Geelong, Victoria, 3220, Australia. 3Orygen Youth HealthResearch Centre, Centre for Youth Mental Health, 35 Poplar Road, ParkvilleVictoria, 3052 Parkville, Australia. 4The Mental Health Research Institute ofVictoria, Australia Kenneth Myer Building, 30 Royal Parade, Parkville, Victoria,
3052, Australia. 5Department of Psychiatry, Melbourne University, Level 1,
North Block Main Building Royal Melbourne Hospital, Parkville Victoria, 3050,
Australia. 6Center for the Study of Complementary and Alternative Therapies,
School of Nursing, University of Virginia, PO Box 800793, Charlottesville, VA
22908, USA. 7Department of Psychology and Neurosciences, Dalhousie
University, 1355 Oxford Streeet, Halifax B3H 4R2, Canada. 8Department ofPharmacology, Chinese Academy Engineering Instit ute for the Developmentof Endangered Medicinal Resources in Southwest China 189 Changgang
Road, Xing Ning District, Nanning, Guangxi Post Code 30023, P. R. China.
9CRC, Rm 30, 57 Laurel street, Glasgow G11 7QT, Scotland, UK. 10Departmentof Adult Psychiatry, Medical University of Łóź, Aleksandrowska 159, Łóź, 91229, Poland. 11Department of Pharmacology, Galway University, University
Road, Galway, Co.Galway, Ireland.
1

Authors’ contributions
MM and MB participated in the design of this review, while all authors
helped to draft the paper. All authors contributed equally to this paper. All
authors read and approved the final manuscript.
Competing interests
There was no financial support for this specific research.
MBk has received Grant/Research Support from the NIH, Cooperative
Research Centre, Simons Autism Foundation, Cancer Council of Victoria,
Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong
Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline,
Organon, Novartis, Mayne Pharma and Servier, has been a speaker for Astra
Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag,
Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvayand Wyeth, andserved as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo
SmithKline, Janssen Cilag, Lundbeck and Servier. The other authors declarethat they have no competing interests.
Received: 23 April 2012 Accepted: 29 June 2012
Published: 29 June 2012
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1741-7015/10/66/prepub
doi:10.1186/1741-7015-10-66
Cite this article as: Maes et al.: Depression and sickness behavior are
Janus-faced responses to shared inflammatory pathways. BMC Medicine
2012 10:66.

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