Inflammation: Depression Fans the Flames and Feasts on the Heat

17 Pages·2015·0.61 MB·English

REVIEWS AND OVERVIEWS
MechanismsofPsychiatricIllness
fl
In ammation: Depression Fans the Flames and Feasts
on the Heat
JaniceK.Kiecolt-Glaser,Ph.D.,HeatherM.Derry,M.A.,ChristopherP.Fagundes,Ph.D.
Depressionandinflammationfueloneanother.Inflammation inflammatory responses. Larger, more frequent, or more
playsakeyroleindepression’spathogenesisforasubsetof prolonged inflammatory responses could have negative
depressedindividuals;depressionalsoprimeslargercytokine mentalandphysicalhealthconsequences.Inclinicalpractice,
responsestostressorsandpathogensthatdonotappearto inflammationprovidesaguidetopotentialtargetsforsymp-
habituate.Accordingly,treatmentdecisionsmaybeinformed tom management by signaling responsiveness to certain
byattentiontoquestionsofhow(pathways)andforwhom therapeuticstrategies.Forexample,athemeacrossresearch
(predispositions)theselinksexist,whicharethefocusofthis withcytokineantagonists,omega-3fattyacids,celecoxib,and
article.Whencombinedwithpredisposingfactors(modera- exerciseisthatanti-inflammatoryinterventionshaveasub-
torssuchaschildhoodadversityand obesity), stressors and stantiallygreaterimpactonmoodinindividualswithheight-
pathogenscanleadtoexaggeratedorprolongedinflammatory enedinflammation.Thus,wheninflammationanddepression
responses. The resulting sickness behaviors (e.g., pain, dis- co-occur,treatingthemintandemmayenhancerecoveryand
turbed sleep), depressive symptoms, and negative health reducetheriskofrecurrence.Thebidirectionallinksbetween
behaviors (e.g., poor diet, a sedentary lifestyle) may act as depression,inflammation,anddiseasesuggestthateffective
mediating pathways that lead to further, unrestrained in- depressiontreatmentscouldhaveafar-reachingimpacton
flammationanddepression.Depression,childhoodadversity, mood,inflammation,andhealth.
stressors,anddietcanallinfluencethegutmicrobiomeand
promoteintestinalpermeability,anotherpathwaytoenhanced AJPinAdvance(doi:10.1176/appi.ajp.2015.15020152)
Depression and inflammation are intertwined, fueling and tobedepressedatage18comparedwiththosewithlowIL-6
feeding off each other. This bidirectional loop, in which de- levels; importantly, IL-6 was measured prior to depression
pressionfacilitatesinflammatoryresponsesandinflammation onset,thussuggestingthathighIL-6isindeedariskfactor
promotesdepression,hasclearhealthconsequences.Height- (12).Inanotherstudywithchildrenwhowere9,11,or13years
ened inflammation characterizes a number of disorders and old at intake, depression predicted subsequent CRP level,
systemicdiseases, including cardiovascular disease, diabetes, with higher CRP levels following multiple depressive epi-
metabolic syndrome, rheumatoid arthritis, asthma, multiple sodes(7).
sclerosis,chronicpain,andpsoriasis;eachofthesealsofeatures However,depression iscomplex,and inflammationmay
anelevatedriskfordepression(1,2). contributeonlyinasubpopulation.DatafromtheNational
Three meta-analyses have highlighted proinflammatory Health and Nutrition Examination Survey provide a rough
cytokinedifferencesbetweenpatientswithmajordepressive estimate of the prevalence of heightened inflammation in
disorderandcontrols,includinginterleukin-6(IL-6),tumor depressedpeople;47%ofthosewhosedepressioninventory
necrosis factor-alpha (TNF-a), IL-1b, the soluble IL-2 re- scores were above the clinical threshold had a CRP level
ceptor,theIL-1receptorantagonist(IL-1ra),andC-reactive $3.0mg/L,and29%hadaCRPlevel$5.0mg/L(13).Raison
protein (CRP) (3–5). The stronger associations in clinical and Miller (14) suggest that inflammatory markers are no-
samples compared with community samples provide evi- ticeably higherinabouta thirdof depressedpatientscom-
denceofdose-responserelationships(3).Supportingacausal paredtothemajorityofnondepressedcomparisonsubjects.
pathway, higher IL-6 and CRP predicted the subsequent Thus, inflammation is neither necessary nor sufficient to
developmentofdepressivesymptoms(6).Relatedly,prospective induceorsustaindepression(14,15),butitclearlyplaysan
studies also showed that depression predicted later IL-6 and importantroleinasubstantialsubpopulation(16).Itfollows
CRP(7–10). that positive clinical responses to anti-inflammatory inter-
The pediatric literature also demonstrates bidirectional ventions may only occur in the subset with heightened in-
pathways between inflammation and depression (11). Data flammation (17, 18). Accordingly, we address mechanistic
from two population-based prospective studies provided pathways between depression and inflammation, and then
evidencefordepression-inflammationrelationshipsearlyin turn to questions of how (pathways) and for whom (pre-
life.ChildrenwithhigherIL-6levelsatage9weremorelikely dispositions) these links exist, with a focus on integrating
ajpinAdvance ajp.psychiatryonline.org 1
INFLAMMATIONANDDEPRESSION
FIGURE1. FactorsThatIncreaseRiskforInflammatoryOverresponsiveness,AlongWithPathwaysLeadingtoHeightenedInflammation,
Depression,andHealthRisksa
Pathways
Sickness behaviors
Depressive symptoms
Negative health behaviors
Gut microbiome
Treatment Options and Responses
Antidepressant medications
Anti-inflammatory agents
Dietary interventions
Exercise
Negative Outcomes
Immune Challenges
Exaggerated or Persistent inflammation
Stress prolonged
Long-lasting depressive symptoms
Pathogens inflammatory
Poor diet responses Further exaggerated responses
Worsened inflammatory comorbidities
Predisposing Factors
Adiposity
History of major depression
Early life stress
Genetic predisposition
aWhencombinedwithpredisposingfactors(moderators),immunechallengescanleadtoexaggeratedorprolongedinflammatoryresponses.Theresulting
sicknessbehaviors(e.g.,pain,fatigue,sleepdisturbance),depressivesymptoms,andnegativehealthbehaviors(e.g.,poordiet)mayactasmediatingpathways
thatleadtofurtherunrestrainedinflammation.Depression,childhoodadversity,stressors,anddietcanallinfluencethegutmicrobiomeandpromote
intestinalpermeability,anotherpathwaytoenhancedinflammatoryresponses.Ultimately,thisoverresponsivenesscouldcarryimportantphysicalandmental
healthrisksandcouldamplifyinflammatoryresponsestosubsequentimmunechallenges.Thispatternsuggestsnoveltreatmentoptionsthatcouldhaltboth
exaggeratedinflammationanddepressivesymptoms,andmayalsohelptopinpointwhichpatientsmightbeexpectedtobenefitfromcertaintreatments.
newerresearchrelevanttodepressioninitiation,treatment depression by simultaneously slowing serotonin pro-
response,andriskforrecurrence(Figure1). ductionandenhancinglevelsofkynurenine,atryptophan
metabolite(22).
Inflammationalsoaffects neuronalgrowthand survival.
MECHANISTICPATHWAYS
Cytokinescontributetooxidativestress,whichdamagesglial
Cytokines induce depressive symptoms by influencing di- cellsinmood-relevantbrainregions,suchastheprefrontal
verse mood-related processes. Elevated inflammatory sig- cortex and the amygdala (23). Cytokine-induced glutamate
naling dysregulates neurotransmitter metabolism, impairs dysregulationcanleadtoexcitotoxicity,therebydecreasing
neuronalhealth,andaltersneuralactivityinmood-relevant production of neurotrophic factors (e.g., brain-derived
brainregions(2,19). neurotrophicfactor,BDNF)thattypicallysupportneuronal
Peripherallyreleasedcytokinessendsignalsviamolecular, health,neuroplasticity,andneurogenesis(24).Notably,these
cellular,andneuralroutes,whichultimatelyreachthebrain neurotransmitter and cellular changes alter brain activity
and enhance CNS inflammation (2, 19, 20). Cytokines alter andneurocircuitsunderlyingdistress,motivation,andmotor
production,metabolism,andtransportofneurotransmitters function(16,19).
thatsynergisticallyaffectmood,includingdopamine,gluta- In addition to their effects on neural processes, cyto-
mate, and serotonin (21). For example, cytokines stimulate kinespromotedysregulatedhypothalamic-pituitary-adrenal
indoleamine 2,3-dioxygenase, an enzyme that affects tryp- (HPA) axis functioning, a key characteristic of depression
tophanmetabolism.Thiswell-establishedpathwaypromotes (25,26).Abnormalglucocorticoidsignalingcaninfluencethe
2 ajp.psychiatryonline.org ajpinAdvance
KIECOLT-GLASERETAL.
maintenance and progression of depression (27). Briefly, who receive interferon-alpha (IFN-a) treatment develop
glucocorticoidstypicallydampeninflammationviaanegative neurovegetative symptoms, including fatigue, sleep prob-
feedback loop. However, inflammation can cause glucocor- lems, anorexia, and psychomotor retardation; these symp-
ticoidresistanceinimmunocytesandtheircellulartargetsby tomspersistthroughouttreatment(21).However,moodand
inducing MAP kinases c-jun N-terminal kinase (JNK) and cognitivesymptomsdevelopprimarilyinvulnerablepatients,
p38 (1). In this way, cytokine signal transduction pathways includingthosewithamooddisorderhistoryorhigherinitial
(e.g., nuclear factor-kB, NF-kB) disrupt glucocorticoid re- levelsofdepressivesymptoms,chronicinflammatoryexposure,
ceptorfunctionandexpression,leadingtounrestrainedin- higherbaselinelevelsofinflammation,orgeneticpolymorphisms
flammatory responses that could further fuel depressive associatedwithriskfordepressionorinflammation(21,38,39).
symptoms (2, 26, 28). Cytokine-dependent glucocorticoid Antidepressantmedicationresponsivenessmaybepoorer
receptor resistance decreases inhibitory feedback on pro- inpatientswithmajordepressionwhohaveheightenedplasma
duction of corticotropin-releasing hormone and cytokines, inflammatory markers, as well as those with polymorphisms
intensifyingthestress-responsesystem(29).Theglucocor- ininflammation-relatedgenesandproinflammatorygene ex-
ticoidreceptorproteinisabundantlyexpressedthroughout pressionprofiles(17,41–51).Recently,aprovocativetrial(17)
the main neuronal subregions of the hippocampus. BDNF assessedtheefficacyofthemonoclonalantibodyinfliximab,
functionsasapowerfulmodulatorofstructuralplasticityin aTNF-aantagonist,in60patientswithmajordepressionthat
the hippocampus and mediates protective influences by was at least moderately medication resistant. Despite the
enhancing neuronal survival (30). Sustained glucocorticoid absenceofanyoverallbenefitforinfliximabversusplacebo,
exposureleadstodendriticatrophyinhippocampalsubfields patients with high baseline CRP levels had substantially
and decreases neuronal cell survival by evoking a decline greaterreductionsindepressivesymptomsthanthosewith
in BDNF expression in hippocampal and cortical regions lowCRPlevels.
(31,32).
Inflammationmayaffectpeopledifferently,dependingon
THEGUTMICROBIOTA,INFLAMMATION,
theirindividualphysiology;somepeoplehavebodilysystems
ANDDEPRESSION
thatprotect themfromdevelopinginflammation-based de-
pression, while others do not. Mechanistically, even lower Thegut-brainaxisinvolvesbidirectionalcommunicationbe-
levelsofinflammationcouldbedepressogenicinvulnerable tweentheCNSandthegastrointestinaltractvia neurocrine
individuals; Raison and Miller (14) call this phenomenon and endocrine signaling pathways (52). Physical and psy-
“immune response element amplification.” These may in- chologicalstressorscanalterthegutmicrobiota’scomposition
clude lower parasympathetic activity, poorer sensitivity to and metabolic activities, and signals produced by the gut
glucocorticoidinhibitoryfeedback,lowerBDNFproduction, microbiotacaninturnaffectthebrainandemotionalresponses
larger responses to social threat in the anterior cingulate (52). Alterations in the gut microbiota shape physiology
cortex or amygdala, and smaller hippocampal volume. In- through contributions to inflammation, obesity, and mood,
deed,theseareallcorrelatesofmajordepressionthatwould amongotherthings(53).Forexample,bothrodentandhuman
influence sensitivity to the depressogenic consequences of studies provide causal evidence linking obesity and the gut
inflammatorystimuli. microbiome(53).
Depression can promote intestinal permeability, that is,
greaterinflammation-inducingendotoxintranslocation,de-
TRAVELINGCOMPANIONS:INFLAMMATION
scribedasa“leakygut.”Indeed,depressedpatientshavebeen
ANDDEPRESSION
found to have higher antibody against gut bacteria than
Thebidirectionallinksbetweeninflammationanddepression comparisonsubjects(54).Inanotherstudy,patientswith
havereceivedconsiderableattention(1,2,16,33–36).Height- majordepressionhadelevatedexpressionof16SrDNA,a
ened inflammation alerts the CNS to induce or intensify marker of bacterial translocation, compared with nonde-
“sicknessbehaviors,”includingnegativemood,fatigue,anhe- pressedcomparison subjects,andthe magnitude was cor-
donia,increasedpainsensitivity,lossofappetite,andcognitive related with depressive symptom severity (55). Among
deficits,aclusterofsymptomsresemblinghumandepression alcohol-dependent patients, those with higher depression,
(29, 34, 37). For example, administration of cytokines, en- anxiety, and craving symptom ratings also had greater gut
dotoxin,orvaccineshasbeenfoundtoworsenmood,fatigue, permeability and gut-bacterial dysbiosis than those with
andpainsensitivityandtoboostproinflammatorycytokine normalgutpermeability(56).
productioninhealthyvolunteers(34). Targeting the gut-brain axis may offer novel treatment
Inflammatorymediatorscanalsoinduceclinicaldepression, options with benefits mediated through the vagus nerve,
bolstering support for inflammation’s role in depression’s spinalcord,orneuroendocrinesystem(57).Dietplaysakey
pathophysiology. These effects can be substantial; for ex- roleinthegut’smicrobiotacompositionandthusrepresents
ample,cytokinetherapies,usedfortreatingsomecancersand onepotentialtherapeuticavenue,asdosupplements(partic-
chronic viral infections, provoke the onset of major de- ularly probiotics and prebiotics) and medications, including
pression in up to 45% of patients (21, 38–40). Most people antibiotics(52).Inrats,probioticpretreatmentattenuated
ajpinAdvance ajp.psychiatryonline.org 3
INFLAMMATIONANDDEPRESSION
gut leakiness after a restraint stressor (58). Limited data caninturnfuelinflammationanddepression,andthusitis
from human subjects suggest that selected probiotics may notsurprisingthattheycanalsopredicttreatmentresistance
reduce depressive symptoms as a result of their anti- andpoorertreatmentoutcomes(68).
inflammatory properties as well as their ability to reduce Pain generates an inflammatory response (69, 70), and
HPAaxisactivity(57). amplifiedpainsensitivityservesasanadditionalinflammatory
Rodent studies show how the microbiota’s composition sourcethatinturnprovokesdepressivesymptoms(71,72).The
haspotenteffectsonbrainbiochemistryandbehaviorearlyin associationappearstobereciprocal:greaterpainisassociated
development(53).Early-lifematernalseparationinmicecan withahigherprevalenceofdepression,andimprovementsin
producebothlong-lastingchangesinHPAstressresponses depression are correlated with declines in pain (73). Pain
as well as persistent microbiome alterations (57), evidence increases the risk for recurrence of depression by worsen-
for one pathway through which early adversity induces ing subthreshold depressive symptoms (74). Greater pain
depressionandinflammatoryresponsesinadults. severityisassociatedwithpoorertreatmentoutcomesinde-
pression,includingpoorerresponsestoantidepressantmedi-
cations(73,74).
EARLYADVERSITY
Disturbed sleep, a cardinal symptom of depression, also
Adults who experienced abuse or neglect as children are hasacontributoryrole,producingatwofoldhigherriskfor
more likely to develop psychiatric disorders (59). Indeed, depression (75). Sleep loss stimulates production of proin-
childhoodmaltreatmentisaparticularlypotentriskfactorfor flammatory cytokines and cellular inflammatory signaling,
depressioninadults,especiallywhenindividualsencounter thus facilitating depression (75). In turn, heightened in-
stressful life events (2, 59). Early adversity also predicts a flammation disrupts sleep regulation (76, 77); pharmaco-
greater risk for recurrent, treatment-resistant depressive logical cytokine blockers can normalize sleep (75). In a
episodes(59). longitudinalstudy,sleepdisturbancesincreasedtheriskfor
Convergent evidence shows that childhood adversity systemicinflammationatthe5-yearfollow-up(78).
can have longer-term inflammatory consequences (60–64). Thus, sleep and pain are additional, independent accel-
Amongadultswithmajordepression,thosewithahistoryof erators for depression and inflammation that also act in
earlymaltreatmenthadhigherCRPlevelsthanthosewithout tandem,buildingoneachother.Disturbedsleepexacerbates
suchahistory(60).Additionally,early-lifeadversitywasstill painandfatigue(79).Conversely,painclearlyimpairssleep
associated with heightened IL-6 and TNF-a in an older (79).Changesinappetite,anotherkeysymptomofbothin-
adultsamplewithameanageof70(61).Adultsurvivorsof flammation and depression, can be triggered by sleep loss
childhoodabusealsohavemaladaptivealterationsintheHPA andfatigue(76,79).Thepoorermood-relateddietarychoices
axisandautonomicstressresponsescomparedwithsimilar that typically follow serve to promote inflammation and
individualswithoutanabusehistory(65).Forexample,those depression.
withahistoryofearly-lifestresshavelowerheartratevar-
iability,reflectinglowerparasympatheticactivity(62),which
DIETASAROADTODEPRESSIONAND
islinkedtoinflammation.Traumasurvivorshaveenhanced
INFLAMMATION
glucocorticoidresistanceandincreasedcentralcorticotropin-
releasing factor activity, further supporting neuroendocrine Observationalstudieshavelinkedhealthierdietswithalower
stressresponsesensitizationinthosewithearlyadversity(65). risk for depression (80, 81). Prospective studies suggest
Furthermore,inflammation-relevantepigeneticalterationsas- that healthierdiets offer some protectionagainstthede-
sociated with earlyadversity include alterations in glucocor- velopment of both depressive symptoms and depressive
ticoidreceptorexpression(62). disorders(82,83).
Earlyadversitycanenhanceinflammatoryresponsiveness Inadditiontoalteringtheriskfordepression,dietquality
tostressors.IL-6levelsrosehigherafteralaboratorystressor also influences inflammation. Patients with metabolic syn-
in individuals who reported childhood trauma compared drome(84)whowererandomlyassignedtoaMediterranean-
withthosewithoutatraumahistory(66).Theselaboratory styledietfor2yearshadsignificantreductionsinCRPand
stressdataparalleldifferencesobservedinresponsetodaily IL-6levels.Inatwinstudy(85),adherencetoaMediterra-
stressors:IL-6levelswere2.35timesgreaterinindividuals nean diet was associated with lower IL-6 levels, and the
with a childhood abuse history who experienced multiple resultswerenotafunctionofsharedenvironmentalvariance
stressors in the past 24 hours compared with participants orgeneticfactors.
withmultipledailystressorsbutnoabusehistory(67). An innovative prospective study (86) addressed the
questionofwhetheraMediterranean-styledietloweredthe
riskofincreasedinflammationovertimeinolderadultswith
SICKNESSBEHAVIORS:PAVINGTHEWAYTO
depressivesymptomsatstudyentry.Atthe6-yearfollow-up,
INFLAMMATIONANDDEPRESSION
the average increase in IL-6 levels was larger in depressed
Sicknessbehaviorsserveanadaptivefunctionbyconserving participantswhohadnotfollowedaMediterranean-stylediet
energyduringanacuteillness(1).However,thesesymptoms thaninallothergroups;incontrast,IL-6levelsdidnotchange
4 ajp.psychiatryonline.org ajpinAdvance
KIECOLT-GLASERETAL.
inthosewhoweredepressedbutfollowedaMediterranean- mood(97).Incontrast,asecondthatfocusedonlyonmajor
style diet, suggesting that the healthier diet buffered the depressionfoundthatomega-3fattyacidshada small,non-
impactofdepressiononinflammation(86). significanteffect(98).Athirddeterminedthatomega-3fatty
Toassessthequestionofwhetherinflammationservesasa acidsupplementationwaseffectiveinbothpatientswithmajor
mediatorbetweendietanddepression,researchersemployed depression and those with subclinical depressive symptoms
an empirically derived inflammatory dietary pattern score (99).Twofurthermeta-analysessuggestedthatEPA,notDHA,
relatedtoCRP,IL-6,andTNF-RII(87).Usingfoodfrequency wasthekeyomega-3fattyacidrelatedtoefficacyintreating
questionnaire data collected six times over 18 years in the depression(100,101),consistentwiththeevidenceforEPA’s
largeNurses’HealthStudy,theyfoundthattheriskforde- stronger anti-inflammatory properties compared with DHA
pressionincreasedwithhigherinflammatoryscoresinwomen (102,103).
whowerenotdepressedatbaseline(87). Epidemiological and observational studies have demon-
Alongwithdietquality,quantityandtimingmatter.Caloric strated that lower omega-3 fatty acid levels are associ-
restrictionproducespowerfulanti-inflammatoryeffectsover ated with higher serum IL-6, TNF-a, and CRP (104–106).
periodsofmonthstoyears(88).Intriguingly,caloricrestric- In contrast, most randomized controlled trials have not
tion is also strongly antidepressant in rodent depression producedreliableserumcytokinechanges(107);thestron-
models(89). gestsupportfortheanti-inflammatorypropertiesofomega-3
Even intermittent fasting or time-restricted feeding can fatty acids in vivo has come from studies with older, hy-
reduceinflammation. Comparisons of IL-6 and CRPin ob- pertriglyceridemic or diabetic individuals with elevated
servant Muslims 1 week before the month ofRamadan (no inflammatory markers (102), as well as a randomized con-
eatingordrinkingduringdaylight),duringthefinalweek,and trolledtrialwithsedentary,overweightmiddle-agedandolder
20 days after Ramadan showed that daytime fasting de- adults(108).
creased IL-6 and CRP levels by about 50% compared with However, inflammatory challenge studies provide com-
pre-Ramadanvalues,adramaticreductionintheabsenceof pelling evidence of protective effects. Omega-3 fatty acids
weightchange;anonfastinggroupassessedatthesametimes have been shown to attenuate both endotoxin and IFN-
showednoIL-6orCRPchanges(90).Time-restrictedfeeding a-induced inflammation and sickness behavior in rodents
alsoreducedinflammationinmice(91).Additionally,TNF-a and humans (109–113). In a randomized controlled trial in
and IL-1ra responses to endotoxin were attenuated in rats which patients received EPA, DHA, or placebo for only
thatfastedfor48hourscomparedwithnonfastedrats(92). 2 weeks before initiation of IFN-a treatment, EPA signifi-
Short-term fasting can also benefit mood. Clinical ob- cantlyreducedtheincidenceofIFN-a-induceddepression,
servational studies have reported reductions in depressive andbothEPAandDHAsubstantiallydelayedonsetofmajor
symptoms that appear between days 2–7 of fasting (93). depression (42). EPA was more effective than DHA, con-
Accordingly,anorexiamayserveanadaptivefunctioninboth sistent with two meta-analyses (100, 101). Importantly, the
clinical depression and inflammation-induced sickness be- studypopulationwassubjectedtoaninflammatoryinsultthat
haviorbyreducinginflammation(94). carriedahighriskfordepression,providingabackdropthat
Thus, cross-sectional, prospective, and randomized- highlightedthereductioninrisk.
controlled-trial research demonstrates how diet quality, Both the results of inflammatory challenge studies and
quantity, and timing influence both depression and inflam- meta-analysessuggestthatheightenedpretreatmentinflam-
mation. Diet-related inflammation can promote depression, mationand/orclinicaldepressionenhancetheoddsofdem-
anddiet-linkeddepressioninturnheightensinflammation. onstrating omega-3 fatty acid-related improvements. The
Onedietarycomponent,fishoil,hasgeneratedconsiderable IFN-atrialclearlyidentifiedimportantbenefitsofomega-3fatty
interest. acidtreatment(42).
OMEGA-3FATTYACIDS EXERCISE
Fishoilistheprimesourcefortwokeyomega-3fattyacids, Considerable evidence supports the value of exercise in
eicosapentaenoicacid(EPA)anddocosahexanoicacid(DHA). treating depression and preventing its onset (76, 114, 115).
Patientswithdepressionhave,onaverage,lowerplasmalevels Physicallyactiveindividualshavelowerlevelsofinflammatory
ofomega-3fattyacidsthannondepressedcomparisonsubjects. biomarkersthantheirsedentarycounterparts(116);reductions
Furthermore,therearerelationshipswithinthesepopulations in inflammation provide one potential explanation for the
betweendepressivesymptomseverityandomega-3fattyacid antidepressantbenefitsofexercise(117).
plasmalevels(95,96). In the Treatment With Exercise Augmentation for De-
Five meta-analysesof randomizedcontrolled trials have pression(TREAD)study,patientswithmajordepressionwho
reacheddifferentconclusionsabouttheefficacyofomega-3 didnotachieveremissionfollowinganadequatetrialofasingle
fattyacidsfortreatmentofdepression.Thefirstconcluded selective serotonin reuptake inhibitor (SSRI) were random-
thatomega-3fattyacidsupplementationbenefitedclinically izedtotwoexerciseaugmentationgroups(118).Thehigher-
depressedindividuals,butnotthosewithlessseveredepressed doseexerciseaugmentationgrouphada28.3%remissionrate,
ajpinAdvance ajp.psychiatryonline.org 5
INFLAMMATIONANDDEPRESSION
compared with 15.5% for the lower-dose group, and effect occurswithadvancingyearsplayaroleintheage-associated
sizeswerethesameorlargerthanthoseobservedinphar- increases in inflammation (128), it was not surprising that
macologicaltreatmentaugmentationstudies(118).Although immunotherapyinducedalethalcytokinestorminagedmice,
fourcytokinesdidnotchangesignificantlyduringthe12-week but not young mice (129). However, in young obese mice,
intervention, higher preintervention TNF-a levels were as- immunotherapyinducedthesamecytokineoverresponsiveness,
sociated with larger decreases in depressive symptoms, and organpathology,andmortalityasseenintheagedmice(129).
changesinIL-1bwerecorrelatedwithchangesindepressive Together, these convergent lines of evidence show how
symptoms(119). stressanddepressioncanactsynergisticallywithobesityto
TheseTREADstudydataareconsistentwithaparadoxin potentiatelargerinflammatoryresponsesthatcouldinturn
the exercise literature. Despite the fact that observational furtherfueldepression.Inadditiontohigherbaselinelevels
studies reliably show that more active people have lower ofinflammation,thesedatasuggestthatobesityalsoconfers
inflammation than their sedentary counterparts (117, 120), riskbygeneratinglargerinflammatoryresponsestostressor
data from randomized controlled trials demonstrating that pathogens. Higher baseline inflammation provides an im-
exercisetrainingreducesinflammationaresparseandin- portantsubstrateforsubsequentexaggeratedinflammatory
consistent (121, 122). In fact, two reviews of randomized responsestochallenge.
controlledtrialsconcludedthatexerciseproduceslittleorno
change in inflammatorymarkersin healthy people who do
PRIMING:CROSS-SENSITIZATIONAMONG
notloseweight(121,122).
CYTOKINES,STRESSORS,ANDDEPRESSION
However,justashigherpretreatmentinflammationpre-
dictedabetterresponsetoaTNF-ablocker(17),theTREAD In addition to early life stress, other major life stressors
studydatasuggestthatexercise’santidepressanteffectsmay function as proximal risk factors for major depression (2).
be greater in those who have higher pretreatment inflam- Both currently and formerly depressed people experience
mation(119).Similarly,theIFN-atrial(42)demonstratedthat moremajorandminorstressorsthanthosewhodonothave
treatment with omega-3 fatty acids was efficacious when adepressionhistory,andcurrentandpastdepressioncanalso
individualsfacedamajorinflammatorychallenge.Ineachcase, boost emotional reactivity to stressors (130–132). Further-
theinitialinflammatoryprofilemadeadifference. more, depression can damage close personal relationships,
akeystressbuffer;bothcurrentandformerlydepressedmen
and women had poorer family functioning than those who
OBESITY
hadnodepressionhistory,evenyearsaftertheirdepression
Depressionpromotesobesity,andobesityinturnpromotes had remitted (133). A history of depression may indicate
depression(1,123).Depressedpeoplehavea58%higherrisk a high-risk phenotype for stress responsiveness (134). Ac-
ofbecomingobese;theriskfordevelopingdepressionover cordingly,apastorcurrentmooddisordercouldactsyner-
time is 55% for persons with obesity (123). Longitudinal gisticallywithstresstoheighteninflammation.
studies suggest that depressive symptoms promote the de-
velopment of the metabolic syndrome, which has central Cross-SensitizationinRodentsandMonkeys
obesityasitscornerstone(124,125). Theclosetiebetweendepressionandstresshasimplications
Depression and obesity have key inflammatory mecha- for inflammation; cross-sensitization between stressors and
nismsincommon.Obesityhasbeencharacterizedasastateof cytokines has been well documented in rats (135, 136). For
chronic inflammationdueto elevatedplasmaIL-6, TNF-a, example,exposuretoanovelenvironment,footortailshock,or
andCRPlevels(1).Whatismore,thepathwaysarebidirectional; evenexposuretoconditionedstimulithatwerepresentduring
visceraladiposetissue’ssecretionofproinflammatorycytokines foot shock all served to enhance IL-6 production (70, 135).
canfunctionasastimulusforHPAaxisactivation,suchthat Furthermore,ratsthathadpreviouslybeenstressedproduced
hypercortisolemiaenhancesadipocyteaccumulation,andvice largerandmorerapidproinflammatoryresponsestoabacterial
versa(124). endotoxinthandidratswithoutapriorstressexposure(135).
Adiposityappearstofuelinflammatorystressresponses. The rats’ endotoxin exposure mimics the immune chal-
Women with greater central adiposity produced larger in- lengesthatoccurfrequentlyindailylife.Forexample,high-
flammatoryresponses toalaboratorystresstaskthan their fatmealscanprovokemildpostprandialendoxemia(137,138)
leanercounterparts(126).Otherauthorsreportedthatboth as well as alterations in gut microbiota and intestinal per-
higherBMIandgreaterbodyfatwereassociatedwithlarger meability(139).
stress-induced IL-6 responses that did not habituate with Thesedata areimportant becausethe physiologicalsys-
repeatedstress(127). tems that respond to endotoxin also respond to behavioral
challenges, and thissharedresponsivity isparticularly det-
InteractiveInfluenceofObesityandAgeinMice rimental when endotoxin exposure occurs in proximity to
Arecentmousestudyhighlightedthejointimpactofobesity psychologicalstress(140).Inrodents,whenendotoxinwas
and age on inflammatoryresponsiveness.Because boththe pairedwithstressorssuchastailshockorrestraint,itsyner-
decreaseinleanbodymassandtheincreaseinadipositythat gisticallyincreasedproductionofproinflammatorycytokines,
6 ajp.psychiatryonline.org ajpinAdvance
KIECOLT-GLASERETAL.
exceedingtheeffectofendotoxinorthestressoralone(141). inflammatory responses have negative mental and physical
Thesituationalcontextalsosubstantiallyaffectedbehavioral healthconsequences.
and immunological responses to low-dose endotoxin in
rhesusmonkeys;thepotencyofthestressorinfluencedthe
ASSESSINGINFLAMMATIONINRESEARCHAND
magnitudeandnatureofendotoxinresponses(140).
CLINICALPRACTICE
Recentmousestudiesprovideprovocativeevidencethat
higherIL-6productionmayinfluencebehavioralresponses Inflammationsignalsresponsivenesstocertaintherapiesand
tosocialstress(48).BothinvivoandinvitroIL-6responses provides a guide to potential targets for clinical symptom
predictedsubsequentbehavioralresponsestorepeatedsocial management. For example, a meta-analysis revealed that
defeat. Mice with larger IL-6 responses to initial aggres- nonsteroidal anti-inflammatory drugs reduced depressive
sorexposurelaterdisplayedastress-susceptiblebehavioral symptomscomparedwithplacebo,particularlytheselective
phenotype (depressive-like behavior) and more persistent COX-2inhibitorcelecoxib;patientswithhigherinflammation
stress-relatedIL-6elevations(48).Thosewithsmallerinitial benefitedmost(152).Similarly,aclearthemeacrossresearch
IL-6 responses were more likely to display subsequent re- with omega-3 fatty acids, exercise, and cytokine antagonists
silient or dominant behaviors. There were also preexisting is that anti-inflammatory interventions have a substantially
immunedifferencesinstimulatedIL-6productionbetween greater impact on mood in individuals with heightened in-
mice that would later display stress-susceptible versus re- flammation.HigherCRPlevelswereassociatedwithabetter
silient behavioral profiles. In further studies, a pharmaco- responsetoescitalopramthantonortriptyline(153).Theanti-
logical IL-6 blockade prevented the development of social depressanteffectsofanti-inflammatoriesmaybemagnifiedin
avoidancebehavior,highlightingitskeyrole(48). patientswithcomorbidpain-relatedorinflammatorydisorders—
Accordingly, preexisting individual differences in IL-6 whichcoverawidespectrum,frompsoriasistocardiovascular
responsivity predict stress vulnerability (48). Importantly, diseasetoobesity.Furthermore,individualswhohaverelevant
because these differences occurred within an inbred, ge- inflammatorygeneticpolymorphismsorgeneexpressionpro-
netically similar strain, both epigenetic and environmental filesmaybemoreresponsivetothesetreatments(38,39,46,49,
factors (e.g., parental transmission of stress sensitivity, dif- 109,154).Itfollowsthatsubstantialinflammatorychanges(and
ferencesinthestabilityofthehomecage’ssocialhierarchy,or benefits)maynotbeobservedinthosewithlowerinflammation
postnatalmicrobialexposures)likelyplayedaprominentrole whoundergothesametreatment.
indevelopingtheseprofiles(142–144). Indeed, a finding that highlights the importance of
heightenedinflammationinthecontextoftreatmentchoiceis
DepressionPrimesInflammatoryResponsiveness thatpatientswithlowerinflammationwhoreceivedaplacebo
Inaccordwiththeanimalliterature,humanstudiesshowthat improvedmorethandidpatientsassignedtoactivetreatment
depressionprimesinflammatoryresponses,promotinglarger inbothinfliximabandomega-3fattyacidtrials(17,18).These
cytokineincreasesinreactiontostressorsandpathogens.For findingsledtothesuggestionthatanti-inflammatorytherapy
example, mild depressive symptoms were associated with may be harmful for patients without inflammation-driven
amplified and prolonged inflammatoryresponses following majordepression(17,18).
influenza vaccination in older adults as well as pregnant Identification of patients who can benefit from anti-
women(145,146).Amongwomenwhohadjustgivenbirth, inflammatory interventions is clearly important. Table 1
thosewhohadalifetimehistoryofmajordepressionshowed lists risk factors for heightened inflammation, an indirect
greaterincreasesinbothserumIL-6andthesolubleIL-6re- waytoevaluateapatient’sinflammatoryphenotype.
ceptorafterdeliverythanwomenwithoutadepressionhistory Forobjectiveconfirmation,theoptimalstrategywouldbeto
(147). Similarly, patients with major depression had larger determinetreatmentbasedonasetofbiomarkers,withIL-6,
increasesininflammatorymarkersthannondepressedcontrols TNF-a, and CRP having the strongest relationships with de-
inresponsetoalaboratorystressor(148,149).Inanotherstudy, pression(3,4).Differencesininflammatorypatternsarelikely,
individualswithmoredepressivesymptomshadlargerstress- giventheheterogeneityofthemajordepressionpopulation(173),
induced increases in IL-6 following laboratory stressors than andthusmultiplebiomarkerscouldprovideaclearerpictureof
thosewithfewerdepressivesymptoms(150). inflammatorystatusthanasingleassay,facilitatingidentification
Studiesthathaveaddressedtheimpactofrepeatedlaboratory ofthebestcandidatesforanti-inflammatoryinterventions(18).
stressorsonIL-6productiondonotshowevidenceofhabituation Forexample,inanomega-3fattyacidtrial,patientswithhigh
(127,151).Thus,ifbothcurrentlyandformerlydepressedpeople valuesonanyoneoffivebiomarkersweremoreresponsiveto
experience more stressors than those without a depression EPA than to placebo, and the EPA-placebo differences were
history(130–132),theywouldlikelycontinuetoexperiencere- larger in those who had multiple heightened inflammatory
peatedexaggeratedinflammatoryresponses. markers(18).Afteridentificationofanti-inflammatorytreatment
JustasindividualdifferencesinIL-6responsivitypredict candidates, additional inflammatory assessments can provide
stressvulnerabilityinmice,theIL-6overresponsivenessin usefultreatmentresponsedata.
people with depression, childhood adversity, and obesity Forroutineclinicaluse,abiomarkerneedstoprovideac-
alsoreflectsrisk.Larger,morefrequent,ormoreprolonged curateandreproducibledatawithwell-validatednorms(174).
ajpinAdvance ajp.psychiatryonline.org 7
INFLAMMATIONANDDEPRESSION
TABLE1. AssessingtheLikelihoodofHeightenedInflammation:RiskFactorsThatRaisetheIndexofSuspicion
RiskFactor Comments
Olderage Inflammationriseswithage(155)
Alargeprospectivestudyshowedthatolderdepressedadultsgainedvisceralfatover5years,while
nondepressedadultslostvisceralfat(156)
Amongthegenesup-regulatedduringlatelife,morethanhalfregulateinflammation-related
processes,onemechanismforexaggeratedproinflammatoryresponses(157)
Early-lifestress Adultswhoexperiencedabuseorneglectaschildrenhaveasubstantiallyheightenedriskfor
inflammationaswellasdepression(60,61)
Lowchildhoodsocioeconomicstatusconfersenduringriskfordepressionandelevatedinflammation,
independentofconcurrentriskfactorssuchasabuseandneglect(158)
Comorbidities Boththenumberandtheseverityofcomorbidinflammatorydisordersordiseasesinfluence
inflammationandriskofdepression;riskisfurtherheightenedbythepainandsleepdisturbancesthat
oftenoccurintandemwiththecomorbidities(159)
Atypicaldepression Atypicalmajordepressivedisorderwithfeaturesincludinghypersomnia,fatigue,increasedappetite,
andweightgainisassociatedwithgreaterinflammatorydysregulationthanmelancholicdepression
(159)
Chronicorrecurrentdepression Amorechroniccourseofdepressionisassociatedwithhigherinflammation(7,160)
Obesity Adipocytes(fatcells)produceandsecreteIL-6andTNF-a,andabdominalfatisamajorinflammatory
source(129)
Centraladiposityandgreaterbodyfatareassociatedwithlargerstress-inducedinflammatory
responses(126,127)
Thereisamedium-sizedrelationshipbetweenbodymassindexandCRPlevelinadults(r50.36)(161)
Poorsleep Sleeplossstimulatesproductionofproinflammatorycytokinesandcellularinflammatorysignaling
(162)
Disturbedsleepaccompaniesmanyinflammation-associatedcomorbidities
Bothdecreasedsleep(,5hours)andincreasedsleep(.9hours)shareamedium-sizedrelationship
withCRPlevel(d50.29andd50.34,respectively)(163)
Unhealthydiet “Western”diets(e.g.,highinredandprocessedmeats;sweetsanddesserts;Frenchfries;andrefined
grains)havehigherassociatedinflammationthanhealthierdiets(e.g.,Mediterraneandiets)(164)
AdherencetoaMediterraneandietwasassociatedwithlowerIL-6levels(85)
Sedentarylifestyle Physicallyactiveindividualshavelowerinflammationthantheirsedentarycounterparts(116)
Bettercardiorespiratoryfitnessisassociatedwithlowerinflammation(165)
Fatigue Fatigue,pain,anddepressionfunctionasatroublesomesymptomclusteracrossmultiplemedicaland
communitypopulations(166)
Likepainanddepression,fatiguehasstrongtieswithinflammation(167)
Pain Paingeneratesinflammatoryresponses(69,70)
Amplifiedpainsensitivityservesasanadditionalinflammatorysourcethatinturnprovokesnegative
affect(69,71,72,168)
Smoking Currentsmokershavehighervaluesacrossmultipleinflammatorymarkersthannonsmokers(169)
Someformersmokershavepersistentlyelevatedinflammationcomparedwiththosewhonever
smoked(169)
Alcoholdependence CRPandproinflammatorycytokinesarehigherinheavydrinkersandabstainersthaninmoderate
drinkers(170)
Femalesex MorewomenthanmenhaveelevatedCRPlevels(171)
IL-6andTNF-aresponsestolow-doseendotoxindidnotdifferbetweenmenandwomen,but
women’sreportsofdepressedmoodandsocialdisconnectionincreasedmorethanthoseofmen,
suggestingthatwomenmaybemoresensitivetoheightenedinflammation(172)
ObesityandCRParemorestronglyrelatedinwomenthaninmen(161)
Sleeplossstimulateslonger-lastingelevationsininflammationinwomencomparedtomen(75)
CRP5C-reactiveprotein;IL-65interleukin56;TNF-a5tumornecrosisfactor-alpha.
Hospital laboratories need standardized assays that provide who may benefit (17, 18), a worthwhile approach for future
replicabledataacrosssites(174).CRPmeetsthesecriteria,but studies.Inaddition,researchersshouldexaminetheextentof
noneofthecytokinesdo,limitingtheirutilityforclinicalpractice inflammatory change and relate it to changes in depressive
atpresent,despitetheirobviousvalue(Table2). symptoms to better understand how lowering inflammation
Anti-inflammatory treatment trials should preselect influencesdepression.
patientswithheightenedinflammation,androutinelyassess
inflammatorychange(175).Surprisingly,inanti-inflammatory
INFLAMMATION’SIMPLICATIONSFORTREATMENT
depression trials to date, heightened inflammation has not
OFMAJORDEPRESSION
been part of the inclusion criteria (175). Using baseline in-
flammationtopredicttreatmentresponsehasprovidedpro- Inflammationisnotubiquitousamongpeoplewithdepression,
vocative data, substantially expanding our understanding of butwhenthetwoconditionsco-occur,treatinginflammation
8 ajp.psychiatryonline.org ajpinAdvance
KIECOLT-GLASERETAL.
TABLE2. InflammatoryBiomarkersCommonlyUsedinDepressionResearcha
Inflammatory
Biomarker Advantages Disadvantages Comments
CRP Routinelyassayedbylocalclinicallabs Lessresponsivetoacutestressthan Synthesizedintheliver,secretedin
Nodiurnalvariation cytokines responsetoIL-6
.5mg/Lriskstratificationvalue Lessreliablylinkedtopsychosocial Half-lifeis15–19hours
suggestedbyliterature(17) stressorscomparedwithother Well-establishedriskstratification
markers valuesandclearclinicalrelevance
forcardiovasculardisease
IL-6 Biomarkermoststronglyassociatedwith Limitedavailabilityinlocalclinicallabs Canbeorderedthroughnational
depression(3) Valuesdependentonassaytypeand laboratories
Mostwidelyusedinflammatory assayprocedureswithinand Half-lifeis,6hours
biomarkerindepressionresearch betweenlabs(4) Riseswithin∼30–45minutesoflab
becauseofitssensitivity Noriskstratificationnorms,values stressors;catecholamines
Responsivetobothacuteandchronic notcomparableacrosslabs increaseIL-6levels
stressors Valuescandifferfromthreefoldto Fastingmorningblooddrawsreduce
upwardsof50-foldbasedon variability
diurnalvariation,recentsleep,and
thedurationandintensityofrecent
exercise(170)
TNF-a Positivelyassociatedwithdepressionin Limitedavailabilityinlocalclinicallabs Canbeorderedthroughnational
clinicalandcommunitysamples(3) Valuesdependentonassaytypeand laboratories
Reliablyelevatedinmajordepression(4) assayprocedureswithinand Fastingmorningblooddrawsreduce
betweenlabs(4) variability
Noriskstratificationnorms,values Targetedbycytokineinhibitor
notcomparableacrosslabs treatments
IL–1ra Positivelyassociatedwithdepressionin Limitedavailabilityinlocalclinicallabs Canbeorderedthroughnational
clinicalandcommunitysamples(3) Valuesdependentonassaytypeand laboratories
assayprocedureswithinand Fastingmorningblooddrawsreduce
betweenlabs(4) variability
Noriskstratificationnorms,values
notcomparableacrosslabs
IL-1b Positivelyassociatedwithdepressionin Notassociatedwithmajordepression Canbeorderedthroughnational
ameta-analysisofclinicaland inameta-analysisofmajor laboratories
communitysamples(3) depressionstudies(4) Fastingmorningblooddrawsreduce
Highlyskeweddistribution,many variability
samplesbelowlimitsofdetection
Limitedavailabilityinlocalclinicallabs
Valuesdependentonassaytypeand
assayprocedureswithinand
betweenlabs(4)
Noriskstratificationnorms,values
notcomparableacrosslabs
aCRP5C-reactiveprotein;IL-1b5interleukin-1beta;IL-1ra5interleukin1receptorantagonist;IL-65interleukin6;TNF-a5tumornecrosisfactor-alpha.
intandemwithdepressioncanenhancerecoveryandreduce provide significant positive long-term benefits for patients
the risk of recurrence. Table 3 includes anti-inflammatory whomakeandmaintainacommitmenttothem.
pharmacological treatments for depression. A meta-analysis Early interventions may be particularly important as a
of the effects of antidepressant medication on cytokines prophylaxisforthosewithpredispositionstodepressionand
showedanaverage50%reductionindepressivesymptoms heightened inflammation. For example, in a randomized
across antidepressants, but only SSRIs appeared to affect study,inflammationwaslowerin17-year-oldswhohadbeen
cytokineproduction(191). assigned to a brief family intervention 8 years earliercom-
Other interventions can also be beneficial. Alcohol de- paredwithcontrols(187).
pendenceandsmokingareoftencomorbidwithdepression, The efficacy of cognitive-behavioral therapy (CBT) in
andbothhavenotableinflammatoryconsequences(169,192); depression treatment is well documented, and CBT may
successfultreatmentofeithercanproducedurablepositive concurrently reduce inflammation (55, 188). In fact, one
changes in both inflammation and depression. Lifestyle in- nonrandomized trial found posttreatment decreases in an
terventions(Table3),includingweightloss,dietarychange, indicatorofintestinalbacterialtranslocationaswellasother
exercise, and some integrative medicine interventions, can inflammatorymarkers(55).
ajpinAdvance ajp.psychiatryonline.org 9
INFLAMMATIONANDDEPRESSION
TABLE3. Anti-InflammatoryTreatmentStrategiesa
InterventionType Advantages Disadvantages Comments
Pharmacological
interventions
Celecoxibandother Maybeusefulasamonotherapy, Riskforgastrointestinalbleeding Patientswithhigherinitial
NSAIDs orincombinationwith withchronicuse,especiallyfor inflammationexperienced
antidepressantmedication olderadultsorthosewhouse greaterbenefitfromcelecoxib
(152) alcohol thanthosewithlower
Celecoxibisassociatedwith Increasedriskofcardiovascular inflammation(152)
betterantidepressantefficacy events Patientswithcomorbidpain-
(responseandremission)than Affectsotherpathwaysinadditionto orinflammation-related
otherNSAIDs(152) inflammation(e.g.,glucocorticoid disordersrespondedbetterto
receptors,adhesionmolecules) NSAIDtreatmentthanthose
withoutsimilardisorders(152)
Cytokineinhibitors Specificallytargetsindividual Reducestheabilitytofightinfection; Treatment-resistantmajor
(e.g.,infliximab) inflammatorycytokines increasesriskofdeathand depressionpatientswithhigh
Treatmentresponsecanbe reactivationoftuberculosis baselineCRPlevelshad
monitoredbyassessingchange Notsuitableforthosewith substantiallygreaterreductions
inthetargetedcytokine immunosuppressiveconditions indepressivesymptomsthan
Cannormalizesleep(75) PatientswithlowerCRPresponded thosewithlowCRPlevels
Cytokineinhibitorshavereduced bettertoplacebothanto Cytokineantagonistsandanti-
depressivesymptomsinpeople infliximab,suggestingthat inflammatorycytokineshave
withpsoriasis(176,177), infliximabmaynotbeappropriate reversedorreducedcytokine-
lessenedfatigueduringcancer forpatientswithoutinflammation- inducedsicknessbehaviorsin
treatment(178),andresolved drivenmajordepression(17) rodents(34)
majordepressioninCrohn’s
diseasepatients(179)
Omega-3fattyacids Higherfishconsumptionis Lessbeneficialinindividualswithout Omega-3fattyacidsattenuated
associatedwithalower aninflammatoryprofile(42,102) bothendotoxin-andIFN-
prevalenceofdepression a-inducedinflammationand
Fewsideeffects sicknessbehaviorinrodents
Benefitsextendtocardiovascular andhumans(109–113)
system(e.g.,lowering EPAappearstobemore
triglyceridelevels) beneficialthanDHA(42,100,
101)
Patientswithalower
inflammatoryprofile
respondedbettertoplacebo
thantoEPA(42)
Prebiotics,probiotics, Probioticsreducegutleakiness Moreinformationisneededonthe Mostofthetreatmentdatacome
andantibiotics andneuroinflammationin particularmicrobiotaalterationsin fromanimalmodels
animalmodels depressedpatientsthatneedtobe
Mayalsoaffectobesity(53) addressed
Initialstudiesinhumanssuggest
thatprobioticsimprovemood
inhealthyadultsandthosewith
irritablebowelsyndromeand
chronicfatiguesyndrome(57)
Lifestyleandbehavioral
interventions
Healthydiets(e.g., Mayconferadditionalbenefits, Dietarychangeandadherencecan AMediterraneandietmayreduce
Mediterraneandiet) suchasreducedcardiovascular beasubstantialobstacle inflammationamong
diseaserisk Somepeoplemayhavelimited individualswithhealthrisks(84)
Healthierdietsoffersome accesstonutritiousfoodsbecause Canbuffertheimpactof
protectionagainstthe ofcostandavailability depressiononinflammation
developmentofboth (86)
depressivesymptomsand
depressivedisorders(82,83)
continued
10 ajp.psychiatryonline.org ajpinAdvance