and pathomechanism Psychological side effects of immune therapies:symptoms ScienceDirect

Psychological side effects of immune therapies:

symptoms and pathomechanism

David Kovacs

, Peter Kovacs

, Nora Eszlari

, Xenia Gonda

and Gabriella Juhasz

Immunotherapiesrevolutionisedthetreatmentofseveral disordersbutshowspecificside-effectprofileswhich frequentlyinvolvepsychologicalsymptoms.Longterm interferon-alpha(IFN-alpha)therapycancausewide-ranging psychiatricside-effectsfromfatigue,insomnia,anxietytofull- blowndepression.Thistreatment-emergentdepressionshares severalsymptomswithmajordepressivedisorder(MDD)witha predominanceofsomatic/neurovegetativesymptoms,andcan betreatedwithantidepressants.However,thisexperience directedresearchtoinflammatorymechanismsinMDD.MDD hasbeenconfirmedasaheterogeneousdisorderwitha subgroupofpatientssufferingfromlow-gradechronic inflammationandfrequentlyresistanttotraditional

antidepressanttreatment.Thusfutureresearchshoulddevelop strategiestoidentifythoseMDDpatientswhocouldbenefit fromdrugsactingthroughinflammatorypathways.

Addresses

1MTA-SENeuropsychopharmacologyandNeurochemistryResearch Group,HungarianAcademyofSciences,Budapest,Hungary

2NationalInstituteofOncology,Budapest,Hungary

3DepartmentofClinicalandTheoreticalMentalHealth,Ku´tvo¨lgyiClinical Center,SemmelweisUniversity,Ku´tvo¨lgyiu.4,Budapest,Hungary

4DepartmentofPharmacodynamics,SemmelweisUniversity,Budapest, Hungary

5NeuroscienceandPsychiatryUnit,UniversityManchester,Manchester, UK

6MTA-SE-NAPBGeneticBrainImagingMigraineResearchGroup, HungarianAcademyofSciences,SemmelweisUniversity,Budapest, Hungary

Correspondingauthor:Juhasz,Gabriella (Gabriella.Juhasz@manchester.ac.uk)

7Equallycontributed.

CurrentOpinioninPharmacology2016,29:97–103

ThisreviewcomesfromathemedissueonImmunomodulation EditedbyFulvioD’Acquisto

ForacompleteoverviewseetheIssueandtheEditorial Availableonline22ndJuly2016

http://dx.doi.org/10.1016/j.coph.2016.06.008

1471-4892/#2016TheAuthors.PublishedbyElsevierLtd.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creative- commons.org/licenses/by-nc-nd/4.0/).

Introduction

Immunotherapyisaspecialbiologicaltherapytargetedat activatingtheinnateimmunesystemtofightinfectionsor

cancer,ordownregulateimmuneresponseincaseofauto- immunedisordersorallergies.Immunotherapiesthatboost immuneresponseagainsttumourcellsorviruses arefre- quently associatedwithearlyneurovegetative symptoms characterised byfatigue, psychomotor slowing, anorexia andpain[1].Thesesymptomsshowasignificantoverlap with the manifestationsof the so-called sicknessbehav- iour,causedbytheactivationofproinflammatorycytokines duringinfectionsandincludingsymptomsoffatigue,an- hedonia, low mood, social isolation and irritability [2].

Sickness behaviour is considered an adaptive response to promotehealing byreducing energy expenditure to- wardsnotnecessaryactivitiesanddecreasingexploratory behaviour, thus it resembles a behavioural pattern very similar toanxiety anddepressive symptoms.Depressive componentsincludinganhedonia,heightenedpainsensi- tivity,andsocialavoidancearemeanttoconserveenergyto fight the infection,while theanxious components were developed to avoid further conflicts which might have negative outcome on thehealing process [3,4]. Thus, an evolutionary advantageous behavioural effect of im- muneresponse,whichenhancessurvival,isalsoadisturb- ingsideeffectoflifesaving immunotherapiesleadingto significantsuffering,burdenandlossofqualityoflife,and thus limiting the completion of the treatment course.

Becauseofthesharpincreaseinthenumberofdifferent immunotherapies and their indications in the present reviewwe focusonthepsychologicalsideeffectsof the mostfrequentlyinvestigatedinterferon-alpha(IFN-alpha) treatment andshortlysummarise the sideeffectsof the newlydevelopedimmunecheckpointblockingagents.

Proinflammatory cytokinesinthe therapy:

IFN-alpha

Interferons are a superfamily of proinflammatory cyto- kinesthatplayaroleinhostdefencemechanisms.IFN- alphaisanaturalcytokinewhichhasasyntheticversion:

IFN alpha-2b. IFN-alpha and IFN alpha-2b bind to interferon type-1receptors,activatingasignaltransduc- tionpathwayleadingtotheexpressionofmultiplegenes responsible for inhibition of tumour cell growth and proliferation [5]. IFN-alpha is widely usedin antiviral, forexample,hepatitisC[6],andantitumortherapiessuch as malignantmelanomaorhairycellleukaemia[7,8].

PsychologicalsymptomsduringIFN-alphatherapy Besidesearlyneurovegetativesymptomswhichmanifest inthemajorityofpatientsduringthefirstweeksofIFN- alphatreatmentas fatigue,painandanorexia,long-term

IFN-alphatreatmentoftencausesawidevarietyofpsy- chiatricside-effects,such as depression,fatigue,insom- nia, anxiety, and cognitive disturbances [1]. 10–40% of patients additionally develop afull depressive disorder syndromethatcanincludesuicidalideation,aboulia,lack ofmotivation,socialwithdrawal,guilt,anhedonia,irrita- bility,anxiety,andcrying[9].Mania,delirium,andpsy- chosisarefurtherbut lesscommonsideeffectsof IFN- alpha treatment. Approximately 30–70% of hepatitis C virus-infected patients treated with IFN-alpha experi- encedifferentdegreesofdepression.Mostofthemsuffer frommild ormoderate depressive symptoms, while se- veremajordepressionoccursinabout15% [10].

In addition to these similarities, the symptom profile (Table 1) oftreatment-emergentdepression andnatu- rally occurring major depressive episode show some distinctions[11].Namely,during long-termIFN-alpha treatmentpatientsreportedmoresevereweightlossand decreasedactivity,whilefeelingofguiltwaslesspromi- nentcomparedtomedicallyhealthydepressedsubjects [12].Thisobservationwassupportedbyarecentfinding whichsuggestedthatriskgeneticvariantintheIL-6gene morespecifically increaseddepressive symptomsmea- sured by the Zung Self-rating Depression Scale com- paredtotheBriefSymptomInventory,suggestingthat inflammatoryriskmechanismsare moreresponsiblefor somatic/neurovegetativesymptomsthancognitive-emo- tional signs of depression [13]. Furthermore, newly developedimmunecheckpointinhibitors,suchasanti- cytotoxicT-lymphocyteanti-gen4(CTLA-4)antibodies or humanised immunoglobulins against programmed death 1/ligand 1 (PD-1/PD-L1) which also enhance tumour-specific immune activity are associated witha

new category of side effects called ‘immune-related adverse events’ (irAE), in which the most frequent symptom is fatigue [14]. However, treatment-induced depressionhasnotbeendetectedinrelationtothesenew drugs[15].

Distressing and frequently untreated depression is a majorcontributortodosagereductionsortreatmentdis- continuationsduringIFN-alphatherapyandconsequent- lyincreasestheriskofineffectivetreatmentoutcomeor relapse[16,17].Thus,itisofgreatclinicalimportanceto investigate the mechanism underlying IFN-alpha-in- duceddepressionandpossiblepreventivestrategies.

PotentialmechanismsofIFN-alpha-treatment-induced depressivesymptoms

IFN-alpha is a strong activator of the proinflammatory cytokinesystembyincreasingtheperipheralconcentra- tionofinterlekin-6(IL-6),interleukin1-beta(IL-1b)and tumournecrosisfactor-alpha(TNF-a)[18].Recentneu- roimaging findingsshowed that acute administration of IFN-alpha elicited aninstant and profounddecrease in brainfunctional networkconnectivity whichresulted in changes in mood and cognitive symptoms [19]. In addition,long-termIFN-alphatreatment wasassociated withincreased glutamate levelin the basalganglia and dorsalanteriorcingulatecortex(dACC)[20]whichmight explainthepreviouslyreportedincreasedACCactivation and impaired error processing in IFN-alpha treated patients[21].

However,remainthequestionhowthecytokineimbal- anceinperipheralplasmasamples,inducedbyIFN-alpha treatment,couldspreadintothebrainwhichisprotected

Table1

Symptomprofileofsicknessbehaviour,majordepressivedisorder,IFN-alphainduceddepression,andpsychologicalsideeffectsof immunecheckpointinhibitors

Symptom domain Symptom Sickness

behaviour

MDD IFN-α ICI

Mood depressed mood x xxx xxx

anhedonia x xxx (x)

guilt x (x)

suicidal thoughts x (x)

Anxiety tension/irritability x x xx

fear x x xx

Cognitive memory/concentration x x

decision making x x

Somatic/neurovegetative appetite x x xxx

sleep xx x x

psychomotor retardation

xx x xxx

fatigue xx x xxx xxx

pain x x xxx

MDD: major depressive disorder, IFN-alpha: interferon alpha treatment, ICI: immune checkpoint inhibitor treatment, x: symptom is present, number of x: dominance of symptoms

MDD:majordepressivedisorder,IFN-alpha:interferonalphatreatment,ICI:immunecheckpointinhibitortreatment,x:symptomispresent,number ofx:dominanceofsymptoms.

by theblood–brain barrier(BBB) (Figure1).There are threemainproposedpathwayshowinflammatoryactiva- tioncanreachthebraintoexertitseffectonmood.First, cytokinemoleculescancrosstheBBBinsomeareasusing specifictransportproteins,andalsobynon-specifictrans- port in thecircumventricularorgans, including thearea postrema,orthesubfornicalorgan.Second,afferentnerve fibres(e.g.vagus)canalsocarrytheinflammatorysignals to thebrain wheninflammatorycytokinesbindto cyto- kinereceptorsandtransmitthesesignalsintothecentral nervous system [22].Third, there isa cellular pathway where whole activated immune cells can reach the brain withthehelp ofCC-chemokineligand 2(CCL2), and CXC-chemokine ligand 1 (CXCL1). Peripherial cytokines, such as TNF, can induce the transport by

activatingthemicroglialproductionofthesechemokines, andalsobyinflammatorystimulatedastrocytes[23].Post mortemstudiesofsuicidevictimswhoalsosufferedfrom depressionrevealedincreasedCCL2expressionandmac- rophage numbers in the perivascular space, suggesting increased transport of activated immune cells into the brain indepressivestate[24].

Decreasedneuralplasticity

BesidesactivatedcellscrossingtheBBB,microglialcells which have the original purpose of fighting infections inside theCNSalso produce cytokinessuchas TNF-a andIL-1b.Overactivationofmicroglialcellsiscommonly reportedinassociationwithdepressivestates.Prolonged elevation of cytokinelevelsinsidethebrain caninduce

Figure1

Social support

Monocyte

Plasticity ROS,RNS Neurotoxicity

Kynurenine IDO Microglia 5-HT

Humoral

Neural

Cellular

T_eff T_reg

NF-KB, BDNF Psychosocial

stress

Pathogen stress

Anti PD-1

Anti CTLA-4

BBB

Morphology AD

IL-1B IL-6 TNF

IFN-α IL-1B

TNF CCL2 CXCL1 IFN-α

therapy

Periphery Brain

Current Opinion in Pharmacology

Potentialroleofimmunemechanismsinimmunotherapy-inducedandstress-induceddepression.Activationoftheimmunesystemduringspecific immunotherapiesorbyinfectionsandsterilestressorslikechildhoodmaltreatment,recentnegativelifeeventsorchronicpaininducesdepression- relatedmechanisms.Theinflammatorysignalofactivatedimmunecellscancrosstheblood–brainbarrier(BBB),andreachthecentralnervous systembyvariouspathways.Themaincoordinatorsofthistransportarethemicroglialcells,producingattractingchemokines,andfacilitatingthe transportofactivatedimmunecellsthroughtheblood–brainbarrier.Microglialcellscanalsobeactivatedbypsychosocialstress.The

proinflammatorysignalinthebrainworksintheoppositedirectioncomparedtotheeffectofantidepressants,suppressing5-HTactivity,and activatingthekynureninepathway.Theneurotoxickynureninemetabolites,andthelowerBDNFandNF-KBlevelspromotereducedneural plasticity,andalsooxidativeradicalsdamageneuralpathwaysleadingtodepression-specificmorphologicalchanges.5-HT:serotonin,AD:

antidepressants,AntiCTLA-4:antibodyagainstanti-cytotoxicT-lymphocyteanti-gen4,AntiPD-1:antibodyagainstprogrammeddeath1/ligand1, BDNF:brainderivedneurotrophicfactors,CCL2:CC-chemokineligand2,CXCL1:CXC-chemokineligand1,IDO:indolamine-2,3-dioxygenase,IL- 1B:interleukin1-beta,IL-6:interlekin-6,INF-a:interferon-alpha,NF-KB:nuclearfactorkB,ROS:radicaloxygenspecies,RNS:radicalnitrogen species,T_eff:effectorTlymphocytes,T_reg:regulatoryTlymphocytes,TNF:tumournecrosisfactor.

neuralapoptoticpathwaysthroughtheireffectonnuclear factorkB(NF-kB)andbrain-derivedneurotrophicfactor (BDNF), resultingin impaired neuronalplasticity, and promoting depression-specific morphological alterations [25].

Decreasedneurotransmitteravailability

Proinflammatorycytokinescanalsoinfluenceneuralplas- ticitythroughtheactivationofindolamine-2,3-dioxygen- ase(IDO)whichistheratelimitingenzymeofkynurenine production.IDOisanenzymewhichconvertstryptophan intokynurenine,thuscompetingfortryptophanwiththe serotonine pathway [26]. Lower tryptophan availability itselfcancausedepressivesymptomsunderexperimental conditions,but lowerserotonergic function is also com- monlyfoundindepressedindividuals.

Increasedneurotoxicity

Besidestheloweramountoftryptophanleftforserotonin synthesis,activationofthe kynureninepathwayalsopro- duces potentially neurotoxic metabolites. For example, quinolinic acid which is elevated in post-mortem de- pressed suicide victims’ brain acts as an N-methyl-D- aspartate(NMDA) receptoragonist,andalsocontributes to disturbances in glutamate reuptake and release from astrocytes, leading to excitotoxic neuronal damage [27].

InterestingtonotethatIDOhyperactivitycorrelatedwith long-termdepression-specificsymptoms(depressedmood, anxiety) but not with early neurovegetative symptoms (pain,fatigue,anorexia)duringcytokinetherapy [28].

Increasedoxidativestress

Inflammatoryactivationisalsoaccompaniedbyincreased productionof radicaloxygen(ROS) andradical nitrogen species(RNS).Theactivityoftetrahydrobiopterin(BH4) whichisnecessaryformonoaminesynthesis,isreducedby oxidativeradicals,suggestinglowersynthesizingcapacity in the presence of inflammation. These oxidative sub- stancesaredamaging forDNA, fattyacids,andproteins alikeespeciallyinneuralcellswhicharethemostvulner- able to oxidative stress.Alterations in neuralcell mem- brane structure, serotonin binding capability, and intracellularsignallingmechanismsduetooxidativestress allcontributetoimpairedserotonergicactivityandtissue damage. Furthermore, superoxide anion radicals (SAR) behaveasaco-substrateofIDOcausingsuperinductionof the kynurenine pathway in the presence of excessive oxidative stress, thus oxidative radicals and kynurenine seemsto forma self-enhancingloop whichreduces the survivabilityofneuronalcellsgreatly[29].

DifferencebetweenthemodeofactionofIFN-alphaand immunecheckpointinhibitors

Althoughboth IFN-alphaand immune checkpoint inhi- bitors increase tumour specific immune response their psychological side-effect profiles are strikingly different.

IthasbeenrecentlydemonstratedthatCTLA-4antibodies

(e.g. ipilimumab) decrease the number of regulatory Tregcellsthroughnon-classicalmonocytes[30].Nonclassi- calorpatrollingmonocytesareresponsibleforclearingup the consequences of inflammation at the vascularendo- theliumandmaintainingtheintegrityoftheBBBthusthey might decrease expansion of the inflammation into the centralnervoussystem[31].PD-1/PD-L1antibodies(e.g.

nivolumab and pembrolizumab, both approved in 2014) increaseeffectorTcellactivitywithintissuesortumours wherecellsexpressPD-1/PD-L1whichtendstobelowin thebrain[14,32].

RiskfactorsofpsychologicalsideeffectsduringIFN- alphatreatment

Ithasbeenobservedthatbehaviouraleffectofinflamma- tion shows differences between patients. Thus knowl- edgeofrisk factorsfor developingdepressionwouldbe usefulinclinicalpracticetopreventsuchadverseeffects [33]. One major risk factor is presence of psychiatric disorders, especially depression in the medical history possibly because of shared biological mechanisms. For example,ithasbeendemonstratedthatincreasedpreva- lenceofdepressioninfemalesmightbeexplainedbythe greatersensitivityoffemalestoinflammatorysignalsboth atthebiochemicalandbehaviourallevel[34].

Potentialgeneticriskfactors

Geneticvariantsthathavebeenimplicatedindepression like theserotonin transportergene functional promoter polymorphism (5-HTTLPR) [35,36], or other serotonin (e.g. HTR1A) or inflammatory (e.g. IL-6, COX-2, TNF- alpha)pathwayrelatedgeneticvariantsincreasetherisk of developing psychological side effects during IFN- alpha treatment [33,37]. Furthermore, several genetic variantsthroughouttheinterferona/bsignallingpathway [38], and genetic variants in the IL-6, IL-1b or nitric oxidesynthase-1 (NOS1) genes increasedepressive and anxiety symptomatology, especially in the presence of psychosocialstressorsingeneralpopulations[13,39,40].

Psychosocialstress

Ithasbeenconsistentlyreportedthatpsychosocialstressis apotent inductorof inflammatoryresponse bothin ani- malsandhumans [41,42].Sterile stressors,like negative lifeevents,areabletoactivateinflammosomes,acomplex cytosolicproteincascadewiththeoriginalroleinpathogen host-defence reaction. The main products of inflammo- somes are inflammatory cytokines such as IL-1B, Il-6, TNF-a,andCRP[22,43].Thesecytokinesareconsidered tobeoneofthemoststablebiomarkersfordepression.In addition,stress exertsnotonly anacutebutalong-term effect on inflammation.For example, childhood trauma permanently upregulates proinflammatory cytokines, probablythroughepigeneticchanges[25,44].Inaddition, patientswithsensitizedstressresponsepathwaysaremore vulnerable to interferon IFN-alpha-induced depression.

For example, patients who responded to a first dose of

IFN-alphawith hyperactivityof thehypothalamic-pitui- tary-adrenalaxis(HPA)weresignificantlymorelikelyto developmajordepressionduringtreatmentthanpatients withmodeststresssystemresponsestotheinitialinjection [45].

Socialsupportasaprotectivefactor

It is important to note that social support is able to decreasetheriskofdepressionbothinageneralpopula- tion andinpatientstreatedwith immunotherapies[46].

Social supporthasbeen associatedwithdecreasedHPA activity and glucocorticoid concentration [47,48], with diminished dACC activityafter socialstressor [48], and withdecreasedproinflammatorycytokineproductiondur- ingstress[49].Indeed,melanomapatientswithincreased social support were less likely to develop depressive symptomsduring low-doseIFN-alphatreatment [50].

PreventionofIFN-alphainducedpsychological symptoms

Screeningandevaluationofriskfactorssuchaspsychiat- richistory,geneticpolymorphisms,premorbidelevations ininflammatorycytokines,orsocialsupportmayhelpto initiatepersonalizedpreventiontherapyinthosewhoare likely to develop psychiatric side effects during IFN- alphatreatment[9].Multiplestudiesfoundthatprophy- lactic andconcurrenttreatment withselectiveserotonin reuptake inhibitors (SSRIs) successfully reduced the incidence and severity of major depression in patients withchronichepatitisCinfectionormalignantmelanoma treatedwithIFN-alpha-2b[51].Inaddition,preliminary studiessuggestthatadietrichinomega-3polyunsaturat- edfattyacidswhichpromoteanti-inflammatoryprocesses inthebodyandmayalsoprocessmood-stabilisingeffects thusmaypreventsomaticdepressivesymptomsincyto- kine-treated patients [52]. However,it is interesting to note that (non IFN-alpha induced) major depressive patientswithanelevatedinflammatorybiomarkerprofile typicallyrespondpoortostandardantidepressantoranti- psychotictreatment [53].

Conclusionsofexperiencewithimmune-influencing agentsfortreatingmajordepressivedisorder

Introductionofimmunotherapieshavenotonlyadvanced thetreatment of tumours,virusinfections,autoimmune diseases andallergies but also shedlight on thepatho- mechanismofdepression.Nowitisincreasinglyaccepted thatmajordepressivedisorderisaheterogeneouscondi- tionconcerningbothitsmanifestationanditsunderpin- nings,andcoversseveraldistinctethiopathologicroutes, oneof thembeingchroniclowgrade-inflammation,that converge to the emergence of similar symptoms [4].

Indeed,SSRI-typeantidepressantsareabletocounteract theeffectofinflammatorymechanismsofdepressiontoa certain degree. For example there is experimental evi- dencethatreleaseofTNF-a,NO,andIL-6frommicro- glial cells in response to IFN-g administration can be

impaired bycertainSSRI-typeantidepressants[54],and they are able to shape the immune response in the peripheralimmunecellsaswell[55].However,asmen- tionedabove,anelevatedinflammatorybiomarkerprofile predictspoortreatmentresponsetofirstchoice(typically SSRI)antidepressants.Forexample,patientswithhigher C-reactiveproteinlevelsimprovedbetteronnortriptyline compared to escitalopram [56]. Thus, patients who are refractoryto standardantidepressant pharmacotherapies shouldbescreenedforinflammatorybiomarkerstoadjust their treatment. Supporting the alternative therapeutic approachtherearestudiesreportingcyclooxygenaseand nitric oxidesynthase inhibitorsexertingantidepressant- likeactivity[29].Inaddition,minocycline,anantibiotic substancewithcapabilityto reducemicroglialactivation wasabletorestorehippocampalneurogenesisandthusa potential candidatein depressiontreatment [57]. More- over, TNF-a antagonistinfliximab showed ahigherre- duction of depression scores compared to placebo in patients with treatment-resistantdepression and higher CRPlevels[58].Thusdrugstargetingtheinflammatory biologicalpathwaysmightbeawayforwardinasubsetof depressed patients who do not improve on standard antidepressanttreatment.

Conflictofinterest

David Kovacs is an employee of Gedeon Richter Plc.

MedicalDivision,butthecompanydidnotprovideany funding,orhadanyfurtherroleinthepreparationofthe article.Theotherauthorsdidnotdeclareanyconflicting interests.

Acknowledgements

ThisworkwassupportedbytheHungarianAcademyofSciences(MTA-SE NeuropsychopharmacologyandNeurochemistryResearchGroup);National DevelopmentAgency(KTIA_NAP_13-1-2013-0001)HungarianBrain ResearchProgram—GrantNo.KTIA_13_NAP-A-II/14;andbythe HungarianAcademyofSciencesandtheHungarianBrainResearch Program—GrantNo.KTIA_NAP_13-2-2015-0001(MTA-SE-NAPB GeneticBrainImagingMigraineResearchGroup).XeniaGondaisrecipient oftheJanosBolyaiResearchFellowshipoftheHungarianAcademyof Sciences.Thefundingbodiesfundedtheworkbuthadnoadditionalrolein thewritingofthisreview.

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