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Title:Antidepressantcoincidentmaniainchildrenandadolescentstreatedwithselectiveserotoninreuptakeinhibitors
Author(s):MeganFJoseph,JairCSoaresandEricAYoungstrom
Source:FutureNeurology.4.1(Jan.2009):p87.
DocumentType:Report
DOI:http://dx.doi.org.vlib.interchange.at/10.2217/14796708.4.1.87
Copyright:COPYRIGHT2009FutureMedicineLtd.
http://www.futuremedicine.com/loi/fnl
FullText:
Author(s):MeganFJoseph1,EricAYoungstrom[[dagger]]2,JairCSoares3
Keywords
adolescentsantidepressantchildrencitalopramfluoxetineinducedhypomaniainducedmaniaparoxetinesertraline
SSRIswitchvenlafaxineyouth
Theincreasinguseofselectiveserotoninreuptakeinhibitors(SSRIs)totreatchildrenandadolescentswithpsychiatric
disordershascausedconsiderablecontroversy[1].Theuseofantidepressantsinyouthstripledbetween1987and1996,
withratesofprescriptionrisingfromthreeper1000totenper1000childrenandteenagersand21per1000youthsinthe
1518yearoldrange[2].AlthoughsomeSSRIshavedemonstratedefficacyundercontrolledconditionsinrandomized
clinicaltrials[3,4],thereisevidencethatmanyofthesedrugsmaynotbeefficaciousingeneralclinicalsettings[57].
Thepotentialbenefitofantidepressanttreatmentneedstobeweighedagainstthepotentialcostsandriskswhendeciding
whethertoprescribe[8].PerhapsthemostsalientconcernisthedebateoverwhetherSSRIscausesuicidalideationor
behaviorinadolescents[9].Althoughtherelativeriskofsuicidewhentakingantidepressantsissmall,suicideissucha
seriousoutcomethatthishasledtotheUKrestrictingtheuseofantidepressantsinchildrentofluoxetineincombination
withcognitivebehavioraltherapy[10].Anadditionalpointofconcernthathasreceivedlessattentionintheliteratureis
thequestionofwhetherSSRIsmayinducemaniaorhypomaniainchildrenandadolescents.Currentevidencesuggests
thatthisisatopicworthyoffurtherempiricalstudy[11],aswellasoneofsignificantclinicalconcern[12,13].Although
maniaisalesssevereoutcomethansuicide,itmaybeamuchmorecommonadverseevent,suggestingthatthepublic
healthburdencouldbesimilar.
Thereareimportantreasonstofocusonreviewingtherelationshipofantidepressantsandmaniainyouths.Although
thereisasubstantialbodyofliteraturesuggestingthatantidepressanttreatmentwithSSRIscancauseanaffectiveswitch
tomaniaorhypomaniainadults[1417],comparativelylittleisknownaboutthisphenomenoninchildrenand
adolescents.Importantly,epidemiologicalevidencesuggeststhatthereisanegativecorrelationbetweenageandriskfor
antidepressantinducedmania[18].Putanotherway,theriskofinducingmaniawithantidepressantmedicationmaybe
especiallyhighforchildrenandadolescents14yearsoldandyounger[19].Youngerageatfirsttreatmentforbipolar
disorderhasalsobeenreportedasapredictorofvulnerabilitytoantidepressantinducedcycleacceleration[20].
Severalfactorsmakeitchallengingtodrawfirmconclusionsbasedontheliteratureregardingantidepressantsandmania.
Oneisthemethodologicalshortcomingsoftheliterature.Thedecisivedesigntoevaluatetheriskofantidepressant
inducedmaniawouldbetotakeagroupofyouths,randomlyassignhalftoantidepressantsandhalftoplaceboandthen
followthemoveralongtimeperiodtoevaluatetherelativeriskofdevelopingmaniawhiletakingantidepressants.
Unfortunately,theavailablestudiesusingrandomandblindedassignmenthavenotusedstateoftheartassessmentfor
manicsymptoms,andthestudieswithbetterassessmenthaveusednonexperimentaldesigns.Additionally,several
limitationsprecludeusinglongitudinalrandomizedcontrolledtrial(RCT)designstoexaminethisissue,including
needingaverylarge(ifnotprohibitive)samplesizeforadequatepowerandthepotentialethicaldilemmaofrandomizing
adolescentstonoantidepressantsforalengthyperiodoftimewhensomebelievetheyareaneffectivetreatment.A
secondissueisthecomplexityofthepossiblerelationshipsbetweenantidepressantsandmania.Mostarticleshavenot
definedaprioriconceptualmodelsortestedcompetingmodelsagainsttheevidence.Thisreviewwilldelineateseven
differentconceptualmodelsthreeofwhichinvolveantidepressantshavinganiatrogeniceffect,twopertainingtothe
natureofbipolardisorderandtwothataredrivenbyartifactsoftheassessmentprocess.Athirdissueisthat,inthe
absenceofdecisivedataandanalyses,thepopularityofexplanationsandthechoicesmadebypractitionersaregoingto
bedrivenbyfactorsbesidesevidence.Intheparlanceofthedecisionmakingliterature,weareforcedtorelyon
heuristicstoguideourpractices,andthesemaybebiasedinpredictablewayssuchasoverestimatingrisks[21].
Thisreviewattemptstoaddressthethreechallengesby:
*RelyingonexplicitcriteriafromEvidenceBasedMedicine[28]forevaluatingthequalityofthestudiesproviding
evidenceaboutthepotentialassociationbetweenantidepressantsandmania
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*Providingspecificconceptualmodelsoftherelationshipthatincludepotentialconfoundsaswellasharmfuleffectsof
medicationaspossibleexplanations
*Qualitativelyevaluatingtheevidencewithregardtoeachmodel
*Qualitativelydescribingtheprovocativenessofeachmodelorthedegreetowhichitmightcaptureattentioninboth
clinicalandpopularaudiencesforreasonsbesidessupportingevidence
*Illustratingaquantitativeapproachforweighingthelikelihoodofhelpversusharm(LHH),againborrowedfrom
EvidenceBasedMedicine[28].
Thereviewcloseswithrecommendationsaboutimprovedassessmentstrategiesthatcanhelpmanagetheriskofmania
duringtreatmentofdepression,aswellasinformingfutureresearchinthisarea.
Modelsoftherelationshipbetweenantidepressants&mania(&sevenpotentialpitfalls&remediesfor
practitioners)
Thefollowingsectiondescribessevendifferentconceptualmodelsofthepossiblerelationshipbetweenantidepressant
medicationsandmanicsymptoms.Foreachmodel,thereisastatementaboutthepotentialassociatedpitfallsfromthe
vantageofthepractitioner,alongwithstrategiestoavoidoramelioratethepitfall.Eachmodelisalsoratedintermsofits
'provocativeness',conveyingthedegreetowhichthemodelislikelytogainattentionowingtofactorsbesidesjustthe
weightofevidencesupportingit.More'provocative'modelsarelikelytoplayuponfearofcausingharm(cognitive
sciencehasdemonstratedthathumanbeingsgivegreaterweighttopotentialrisksthanbenefitsindecisionmaking)ora
senseofscandal.Moreprovocativemodelswouldbeofconcerntopractitionersandwouldalsoreadilyattractthe
attentionofmediaoutletsthatareperhapsfirstconcernedwithpopularappealabovescientificevidence.Conversely,less
provocativemodelsmayhaveamoredifficulttimecapturingimaginationsandgainingbroaddissemination,evenifthey
happentobeaccurate.Next,weevaluatethedegreetowhichthemodelinquestionissupportedbytheavailable
evidence.Theratingsattachedtotheprovocativenessand'likelihood'obviouslyincludealargedegreeofsubjectivity.
Wedonotpretendthattheyarecompletelyobjectiveorpreciseanddidnotrelyonformalcodingcriteria,butweintend
themtobeaconciseandclearwayofcommunicatingourimpressionsbasedonaqualitativereviewoftheliterature.We
alsowanttobeclearthattheterm'likelihood'isnotintendedtoconnoteanyformalstatementaboutprobability(i.e.,a
scoreof6doesnotmeanthatthereisa6/7chancethatthetheoryiscorrect).Finally,wepresentsomepotentialresearch
designsthatcouldmoreinformativelytesteachofthedifferentmodels.
Ignitionhypothesis
Uncoveringalatentdiathesis,turningongenesthatwerealreadypresent.Thetinderofbiologicalandenvironmentalrisk
factorswerealreadypresentandtheexposuretothemedicationprovidedthesparknecessarytolightthebipolar
'blaze'.TherehasbeenadramaticincreaseintherateofdiagnosisofbipolardisorderintheUSA[22,23],leadingto
speculationthatthehigherratesmay,inpart,beattributabletothehigherrateofmedicationprescriptionintheUSA
ignitingalargeramountofmaniainthepopulation[24].Potentialpitfall:selectinganagentthatisalogicalchoicefor
thepresentingsymptomsbutdestabilizesthepatient.Remedy:carefulassessmentofriskfactors,carefulmonitoringof
possibleswitchorbreakthroughmaniaandrapidchangeinpharmacologyaftermanicsymptomsemerge.
Provocativeness(17,with7beingthemostprovocative):5.TheIgnitionhypothesisisthescenariomostwidely
discussedatmeetingsandinthepopularpressisthereasubsetofpatients(thosewithbipolardisorder)whoactually
arelikelytobeharmedbyfrontlinetreatmentsfordepression?Europeanregulatoryagenciesandothergroupsare
concernedthatthehigherratesofpediatricmaniaintheUSAmaybeatleastpartiallyattributabletothehighratesof
exposuretomedication[24].Likelihoodbasedonavailableevidence:4.Informativewaytoevaluate:demonstrategene
compoundinteractions.Thishasnotyetbeendoneinpsychiatry,butcouldbeaccomplishedbyaddinggenotypingto
PhaseIIItrials,orbypersonalizedmedicinedataminingapproaches(comparingthegenomeagainsttreatmentadverse
effects).Forexample,workinTypeIIdiabeteshasrevealedgeneticpolymorphismsassociatedwithedema,orfluid
retention,asideeffectofdrugtreatment[25].Studiessuchasthesefrombranchesofmedicineotherthanpsychiatry
suggestthatlinkinggeneticinformationwithmedicationsideeffectsispossible.However,duetolowbaseratesofmania
asasideeffect,theseapproacheswouldrequirehugesamplesizes,thoughthesearebeingbuiltrapidly,andalsomore
systematiccodingofmanicsymptomsthanistypicallydone.Ideally,anypharmacogeneticresearchinthisareawould
alsotakeintoaccountenvironmentalfactorshowever,thisisdifficultonalargescaleandexamininggeneby
medicationinteractionsmaybemorefeasible.
Scarhypothesis
Creatinganewdiathesisintheabsenceofpriorbiologicalrisk.Potentialpitfall:causingharmwithwellintentionedand
logicaltreatmentfordepression.Remedy:carefulassessmentofriskfactors,intensemonitoringtodetectemergent
mania,andarapidswitchinpharmacology.Provocativeness:7.Thisisthescarymonsterlurkingintheclosetfor
prescribers.Takeonebrain,previouslyincapableofdevelopingmania,treatitfordepressionandleaveitpermanently
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vulnerabletomanicepisodes.Likelihoodbasedonavailableevidence:2.Therearenodecisivestudiesrefutingthis
possibility.However,therearemanyotherscenariosthatappearmuchmoreplausible,bothascausesofmanicsymptoms
andalsobecausetheideathatbriefexposuretoacompoundcouldproducepermanentdeleteriouschangecontradicts
growingknowledgeoftheplasticityoftheCNSanditstendencytosurviveandrecoverfrominsult.Informativewayto
evaluate:demonstratechangesinbrainmorphologyorpathophysiologyfollowingmedicationexposure,andshowthat
thesepredictrecurrencesofmania.Itwouldbedecisiveifitcouldbedemonstratedthatthesechangesoccurafter
exposuretothecompoundevenintheabsenceofestablishedgeneticriskfactorsforbipolardisorder.
Sideeffecthypothesis
Temporarydeleteriouseffectofthedrug,butnotatruemanifestationofabipolarillness.Potentialpitfall:theerror
wouldbeinattributingthesymptomstoadiseaseinsteadoftheimperfectdrug.Remedy:avoidlabelingpeoplewith
manicsymptomsoccurringwhiletakingantidepressantsashaving'bipolardisorder'.Atpresent,theDiagnosticand
StatisticalManualofMentalDisordersIVTextRevision(DSMIVTR)indicatesthattheseeventsshouldbecodedas
'substanceinducedmania'ratherthanaformofbipolardisorder[26]becauseofthepossibilitythatthesymptomsarea
sideeffectratherthananunmaskingofabipolardiathesis.Theclinicalmanagementtypicallywouldinvolvechanging
pharmacotherapyandusingintensiveassessmenttoevaluatewhethermoodsymptomspersistataproblematiclevel.
Provocativeness:3.TheSideeffectargumentmotivatedsomehighprofilelawsuitsbackwhencompoundswerefirst
introduced,butthisscenariohasdefinitelybeeneclipsedbytheIgnitionandScarhypothesesinrecentdiscussions.The
'sideeffect'modelislessfrighteningbecauseitpositsthattheharmfuleffectsofthecompoundarelimitedinduration
(orelseittransformsintotheScarHypothesis).Likelihoodbasedonavailableevidence:4.Informativewaytoevaluate:
ABABdesign,alsoknownasachallengewithdrawalrechallengestudy,todemonstratethatsideeffectsonly
happenwhenexposedtotheagent.TheSideeffecthypothesiswouldalsobesubstantiatedbyeithershowingthatmanic
symptomsoccurintheabsenceofgeneticriskforbipolardisorder,orbyshowingthatthepathophysiologyofsideeffects
isdifferentfromthepathophysiologyofbipolardisorder.
Vigilancehypothesis
Increasedmonitoringfortheillness,butnoactualchangeinrisk.TheVigilancehypothesisisavariantof'verification
bias',whichplaguesmedicalassessmentandrepresentsaseriousthreattothevalidityofanystudieswithoutblinded
evaluationandastringentlydefinedcomparisongroup(ideallybasedonrandomassignment)[27,28].Potentialpitfall:
confusingheightenedmonitoringwithincreasedrisk.Fallingvictimtoacognitiveheuristicandrememberingthecases
wheremaniaoccurred,butdiscountingthecaseswhereitdidnotoccurwhileusingantidepressants.Remedy:evaluateall
patientsonantidepressantsforpossibleemergenceofmanicsymptomsavoid'workup'bias.TheUSFDAnow
recommendsevaluationforpossiblebipolardisorderwhenprescribingantidepressantmedications,althoughthe
suggestedlanguagecurrentlyfallsshortofa'blackbox'warning[101].PractitionerscanfindreviewarticlesandRCTs
andlearnriskratesfromthem.Provocativeness:1.Thereisvirtuallynothingexcitingorglamorousaboutthevigilance
scenario,anditisunpopulartoberemindedthatweareimperfectatweighingandcombininginformation[29].
Likelihoodbasedonavailableevidence:5.Aswewillsee,studieswithstrongerdesignstendtofindlowerratesof
treatmentemergentmania.Additionalargumentsinfavorofthispossibilityare:first,theinaccuracyofmanyclinical
diagnosesofbipolardisordersecond,theinadequacyofmanyclinicalevaluationsintermsofascertainingfamilyhistory
orpriorhistoryofhypomania[cf.30,31]andthird,thefailureofmostclinicianstoconsiderbipolardisorderasa
possibilityinyouthsuntilrecently,andthewidelyunevenimplementationofconsistent,evidencebasedpracticesaround
thecountry,evenatpresent.Informativewaytoevaluate:researchstudyconductingsameintensityoffollowupfor
thoseexposedtoantidepressantsversusothercompounds,orsystematicallyvaryingtheintensityoffollowupforthe
sameantidepressantmedication.Presentingclinicianswithcasevignetteswherethecontextinwhichsymptomsare
presentedisvariedcouldalsobeinformative.Ideally,userandomassignmentandalargetrialtoequategroupson
characteristicsbesidescompound.
Medicationasirrelevanthypothesis
Whatwearewitnessingisthenaturalcourseofthebipolarillness,notaresponsetothetreatment.The'naturalcourse'
confoundiswidelyrecognizedasarivalhypothesisinmethodologycirclesthatpotentiallyaffectsanydesignexceptfor
arandomizedtrial[32,33].Inthecaseofbipolardisorder,thepossibilitythatchangesinmoodareduetothenatural
courseoftheillnessisnotavagueacademicpremiseitisawelldocumentedclinicalphenomenon.Potentialpitfall:
blamingatreatmentforaneventthatwascompletelyunrelated.Remedy:findandrelyonwelldesignedresearchabout
riskstoavoidheuristicsandclinicalillusionsaboutclinicalphenomena.Provocativeness:1.Thereisnoelementof
intrigue,noblametobeassignedtothecompoundorthepractitioner,exceptperhapsfailingtorecognizethe'great
masquerade'ofmentalillnessinitsfirstguises.Likelihoodbasedonavailableevidence:6.Informativewaytoevaluate
:combinestudieslookingatantidepressantcoincidentmania(ACM)incaseswithbipolardisorderrandomizedtoeither
antidepressantorplacebo(realistically,bothasadjuncttoanothermoodstabilizingcompound)thiswouldhelprule
outacausalroleofthecompound.Goodepidemiologicalandnaturalhistorystudiesarealsoneededtounderstandrates
ofhypomania(sorelylackinginepidemiologicalstudies)andratesofrecurrence[cf.34].
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Falsealarmshypothesis
Mislabelingjuvenilebehavioraspathologicalwhenitstillfallswithinnormallimitsmistakingaggressivebehaviordue
toothercausesaspediatricmania[35]oralternatively,mistakingthereturnofenergyandpositiveemotionsas
depressionliftsforhypomania.Potentialpitfall:attributingbehaviortoadiseasethatisnotpresent.Remedy:use
assessmenttoolsthatextendbeyondtheroutineclinicalinterview,especiallytoolsthatrelyonagenormsordirect
comparisonstootherclinicalsamples.Adopt'probabilityofdiagnosis'approachfromEvidenceBasedMedicineto
acknowledgewhencasesareambiguousinsteadofclearcut[28].Provocativeness:6,ifyouareskepticalaboutthe
diagnosisofpediatricbipolardisorder2ifclinicallyactiveinthearea.TheFalsealarmhypothesisappealstothoseready
tojumponthe'pathologizingchildhood'bandwagon[36],aswellasplayinguponconcernsabouttheoverdiagnosisof
bipolardisorder[36].Thosewhoworkinclinicalsettingsorconductresearchwiththeseyouthsencountersevereenough
impairmenttomakethe'justbeingakid'explanationimplausibleinmostcases.Likelihoodbasedonavailable
evidence:2.Informativewaytoevaluate:muchworkhasbeendonevalidatingtheconstructofpediatricbipolar
disorder[3739].Basedonthevaliditydata,itisclearthatatleastsomecasesofmaniareflectanunderlyingbipolar
illness.Conversely,therearedefinitelycasesthatarelabeledandtreatedas'bipolar'whenitisacompletelydifferent
processleadingtothesymptoms.Carefulindividualassessmentisthebestwayforward.
Bipolardepressionhypothesis
Earlyonsetdepressionisariskfactorforbipolardisorder[4042],andmanypeoplewithbipolardisorderfirstseek
treatmentduringadepressedepisode[43,44].Thesefindingssuggestthatwhentreatingyouthsfordepression,weare
oftendealingwiththedepressedphaseofwhatwillprovetobeabipolarillness.Potentialpitfall:blamingtreatmentfor
thenaturalcourseoftheillnessfailingtorecognizebipolardepression.Remedy:assessment,againcarefullyevaluate
familyhistoryofbipolardisorder,assessforpriorhypomaniasormaniasassessformixedstates.Provocativeness:5.
Theappealwouldcomefromthestealthfactor,thattheillnesshasbeenavoidingdetectionpreviously(contradicting
currentconcernsaboutoverdiagnosisofbipolardisorder).Likelihoodbasedonavailableevidence:6.Informativewayto
evaluate:attheresearchlevel,studiesareneededthatcarefullyfollowchildrenandteenagerswithdepression
prospectively,tofindhowmanyofthemdevelophypomaniaormania.Thenextgenerationofresearchneedsto
incorporatestrategiestoaccuratelydetecthypomania,whichhasbeentheAchillesheelofpriorresearch,leadingtothe
ambiguitiesforbipolarIIandcyclothymicdisorder.Asimilardegreeofsophisticationabouthypomaniaalsoneedstobe
deployedinclinicaltrialsofantidepressants,especiallyplacebocontrolledstudies.
Guidelinesforevaluatingstudiesofharm
TherehasbeenamovewithinthefieldofEvidenceBasedMedicinetodevelopasetofguidelinesorcriteriafor
evaluatingstudiesquickly,gaugingtheirdesignandappraisingtheirvalidityandrelevanceforindividualpatients.These
includetheConsolidatedStandardsofReportingTrials(CONSORT)criteria[32]forclinicaltrials,aswellasaseriesof
briefarticlesthatappearedasaseriesinJAMAbeforebeinganthologizedandexpanded[45].Perhapsthemostaccessible
discussionoftheseguidelinesandtheirapplicationtoindividualcasesisofferedinthebook,'EvidenceBased
Medicine'[28].Ifantidepressantsdoinfactincreasetheriskofmania,itwouldbeanexampleoftreatmentcausing
harm.Box1providesasetofcriteriaforevaluatingwhethertheevidenceaboutantidepressantscausingharminother
words,inducingmaniaisvalid(adapted[28]).Wewillrefertothesecriteriawhenevaluatingthepublishedstudies.
Reviewoftheevidenceforantidepressantspotentiallyinducingmania
Antidepressantinducedmaniainadults
Antidepressantinducedmaniaisawellknownclinicalphenomenoninadults[14,15].Metaanalysissuggeststhat
approximately3.7%ofindividualswithunipolardepressionmayexperienceaswitchtomaniafollowingexposuretoa
SSRI[46],while2444%ofindividualswithbipolardisordermayexperienceanaffectiveswitchwhiletakinganSSRI
[17,47].Importantly,adults(andchildren)withbipolardisordertypicallyspendalargerpercentageoftimedepressed
thanmanic/hypomanic[48,49],suggestingthattreatmentofdepressionmaybethemostimportantaspectof
psychopharmacologicalmanagementofbipolardisorder[11,50,51].
ManiacoincidentwithSSRIusageinyouths
ThenextportionofthereviewconcentratesontheliteraturepertainingtomaniaandSSRIsinyouths.Wefocusedon
SSRIsbecausetherelativelybenignsideeffectprofilehasmadethemalmostuniversallypreferredtothecyclic
antidepressantsandmonoamineoxidaseinhibitorsinpediatricsamples[2,52].MedlineandPsycInfoweresearchedusing
theterms'childrenoradolescentsoryouth','mania','SSRI','inducedmania'and'antidepressantinduced
mania'.Additionalreferencesweregatheredfromthereferencelistofidentifiedarticles.Thissearchstrategyidentified
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36articlesforthereview.
CasestudiesofpediatricmaniacoincidentwithSSRIusage
TherearemanycasestudiesdescribingantidepressantinducedmaniainchildrenandadolescentstreatedwithSSRIs,
includingcitalopram(fivecases)[53,54]fluoxetine(11cases)[5559]paroxetine(sevencases)[6063]sertraline(five
cases)[6467]andvenlafaxine(aserotoninnorepinephrinereuptakeinhibitoronecase)[69].Thesereportsdescribea
youngpersontreatedforanxietyordepression(andinonecase,epilepsy)[53],whodevelopedsymptomsofmaniaor
hypomaniaaftertreatmentwithanSSRIforperiodsoftimethatweretypicallyshort(8weeksorfewer)[54,5662,6466]
,butweresometimeslong(from5monthstoayear)[53,57,58,63].Themediantimetoonsetofmaniawas21days,witha
rangefrom2to365days.Theseindividualsvariedintermsoffamilyhistory.Atotalof21%hadafirstdegreeorother
relativewithdiagnosedbipolardisorder45%didnothaveafamilyhistoryofmooddisorders.
Theonsetofmania/hypomaniausuallyfollowedthecommencementoftheSSRI,butinsomecasesitwastheresultofan
increaseindoseafterthepatienttoleratedlowerdoses.Cessationofantidepressanttreatmentledtoaresolutionofthe
manic/hypomanicsymptomsin59%ofcases,whileamoodstabilizerwasusedin38%ofthecasesinordertomitigate
symptoms[5355,57,59,62,65,67,68].Nearlyallcasestudiesreportedthatfollowingthecessationofthemanicsymptoms,
thepatientthenremained'stable',typicallyoffoftheantidepressantorsometimesatalowerdosethepatientmayhave
continuedonamoodstabilizerifonehadbeenadded.However,theperiodoftimeforwhichtheywerefollowedvaried
amedianof20weekswitharangefrom2to52weeks.
Takenasawhole,thesecasestudieswouldseemtosuggestthatcautioniswarrantedwhentreatingchildrenand
adolescentswithSSRIs,astherearedocumentedcasesofthistreatmentcoincidingwithmaniaorhypomania.However,
itisalsoimportanttokeepinmindthatmooddisordersshownaturalfluctuations(withthe'Medicationasirrelevant'
hypothesisrepresentingtheextremeviewthatwhatappearstobetreatmentemergentmaniaisactuallyjustabipolar
illnessfollowingitsownnaturalcourse,independentofthepresenceorabsenceofantidepressantmedication),and
thereforecausallinkstothedevelopmentofmanicsymptomsbytheadditionofanSSRI,orresolutionofmanic
symptomsbyremovaloftheSSRI,cannotbeestablishedbycasestudies.Thepharmacokineticsofantidepressant
medicationsmaketheuseofABABdesigns,whichcanbehelpfultoolsforestablishingcausalityorefficacyatthe
individuallevel,difficultowingtothelonghalflivesandresultinglengthoftimeneededtotitrateorwashout
medication.Additionally,casestudiesareprobablyabiasedsourceofinformation,astheyarewrittenaboutpatientswho
standoutintheclinician'smind.ReportsofyouthstreatedwithSSRIswhodonotdevelopmaniadonotappearinthe
researchliteratureascasestudies.Thesameheuristicmayalsooperateattheleveloftheindividualclinician:itismuch
morememorablewhenacaseshowsanadverseeventsuchasmaniaversusacasethatdoesnotandhumansasdecision
makersarepronetogivingmuchgreaterweighttonegativeeventsasanevolvedheuristicforavoidingrisks[69].
ChartreviewstudiesofSSRIinducedmania
SeveralchartorcasereviewshaveattemptedtoexaminetherelationshipbetweenSSRItreatmentandmaniainmore
systematicways.Somestudies'findingssuggestthatantidepressantsmightincreasetherateofmania.Faedda,
Baldessarini,GlovinskyandAustinreportedarateof48.7%ofchildrenwithbipolardisorderdevelopingmania
followingtreatmentwithaSSRI(n=19of39exposed)[70].Theantidepressantinducedmanicepisodewastheepisode
thatinitiatedthebipolardiagnosisinonly17%ofthosecases.Themedianlatencytomaniawas12.5days(acrossall
classesofantidepressantsandstimulants).Anotherchartreviewofyouthswithbipolardisorderrevealedthatthose
receivingSSRItreatmentwerethreetimesmorelikelytoreportmanicsymptomsattheirnextfollowupvisitthanyouths
whodidnottakeaSSRI[71].Wilensandcolleagues,whenreviewing82consecutiveadmissionstoapediatric
psychopharmacologyunitwhowereprescribedanSSRI,foundthatfiveoftheyouth(6%)haddevelopedmanic
symptomswhiletakingtheSSRI[72].Areviewof79consecutivehospitaladmissionsshowedthatyouthswhohadever
receivedanantidepressanthadanearlierageofonsetofbipolardisorderthanyouthswhohadnot[73].However,the
latterstudydidnotlookattheeffectoftreatmentwithaSSRIseparatelyfromotherclassesofantidepressants.The
patternoffindingsinthesestudiescouldbeexplainedbytheIgnitionorScarhypotheses,butitalsoisconsistentwiththe
Bipolardepressionhypothesis:youthswithbipolardisordermightoftenhaveearlieragesofonsetfortheirdepression,
leadingtoearlierantidepressantprescription.Anotherchartreviewstudyexamined'druginducedbehavioral
disinhibition',andfoundthatratesincreasedsignificantlywithSSRIusage[74].Astrengthofthisstudywasthatit
includedobjectivebehavioralindicators,suchasnumberofseclusionsbutitisnotclearhowmuchoverlapthereis
between'behavioraldisinhibition'andmania.
Apharmacoepidemiologicstudyofageeffects[18]examinedconversiontomaniainchildren,adolescents,andyoung
adultswithanxietyornonbipolarmooddisorders.Theauthorsanalyzedmentalhealthoutpatientandpharmacyclaimsof
87,920individuals,aged529years,overamedianof41weeks.Thestudyshowedanoverallprevalenceofmanic
conversionof5.4%.Atotalof49%oftheconvertershadbeenexposedtoaSSRI.SSRItreatmentwasassociatedwitha
hazardratioof2.1,roughlyatwofoldincreaseintheriskofconversiontomania.Thiseffectsizeisconcerning,yetalso
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smallenoughthatEvidenceBasedMedicineauthoritiespointoutthatitcouldbeentirelyattributabletoextraneous
factorsbesidesaniatrogeniceffect[28].TheauthorsreportedthatamongthosetreatedwithSSRIs,youthyoungerthan
15yearsofagewereatanincreasedriskformania.Again,thisdesigncannotdistinguishbetweentheBipolardepression
hypothesisversusthethreeiatrogenicpossibilities.
Inoneofafewstudiesspecificallyexaminingantidepressantinducedmaniainyouthswithbipolardisorder,Baumeret
al.foundthatamong52childrenandadolescentswithoratriskforbipolardisorder(operationalizedbyhavingaparent
withbipolardisorder),50%experiencedeitheranewmanicepisodeoraworseningofanexistingepisodeafterbeing
treatedwithvariedantidepressants,approximately80%ofwhichwereSSRIs,foranaverageof1.4years[11].Inachart
reviewstudythatfollowedyouthsfor12monthsafterfirsthospitaladmissionforeitheramanicoramixedepisode,
antidepressantusewasassociatedwitharecurrenceofamoodepisode[75].Thereportingofthisstudydidnot
differentiatebetweenmanicversusdepressedrecurrence,though,andotheraspectsofthefindingsindicatethattreatment
refractorinessofdepressionmightbeinfluencingresults.
Otherstudieshavefoundnoeffectofantidepressantsontheageofonsetofbipolarorthemanicsymptomsobservedin
youthswithbipolardisorder,includingretrospectiveinterviewreportaboutageofonsetandcurrentinterviewbased
moodratingsinanoutpatientsetting[76].Similarly,Soutulloandcolleaguesfoundthatamonghospitalizedadolescents
withbipolardisorder,ahistoryofexposuretoantidepressanttreatmentwasnotassociatedwithamoreseverecourseof
hospitalizationasmeasuredbylengthofstayinthehospital,numberof'asneeded'medicationsgiven,orseclusionand
restraintorders[77].Attheotherextreme,astudyofyouthswithpsychoticdepressionfoundthatantidepressantusewas
associatedwithafourfolddecreaseinriskofdevelopingmaniaoverthefollowupperiod,withcasesfollowedforas
longas2years[78].
Alongitudinalstudylookingatthedevelopmentofmaniainacohortofyouthsoriginallyidentifiedashavingattention
deficit/hyperactivitydisorderbutnocomorbidmooddisorderisalsorelevant[79].Theyouthswereoriginallyascertained
asacomparisongroupforalongitudinalstudyofpediatricbipolardisorder,with6yearfollowupdataprovidingthe
basisforanalysis.Basedonblindedinterviews,29%developedbipolarIwithelationorgrandiosity.Antidepressantuse
wasnotsignificantlyassociatedwithdevelopingmania.ThesefindingscouldbeconsistentwiththeBipolardepression
hypothesis:systematicallyexcludingcaseswithpediatricdepressionmayhaveeliminatedcasesinitiallyidentifiedas
depressedwhowouldlaterhavecycledintomania.Excludingthesemighthaveeliminatedtheartifactthatisinterpreted
asshowinga'switch'tomaniainotherstudies.
Inshort,thechartreviewstudies(includingthosewithfollowup)havefoundinconsistentresults,andthedesignshave
notbeenstrongforexaminingtheissueofantidepressantusageprecipitatingmania.Thestudieswithafollowup
component,highretentionandthemoststructuredassessmentsofmaniahavetendedtoproducethesmallesteffects.
Overall,thesefindingsappearmostconsistentwiththeVigilanceandBipolardepressionhypotheses.TheMedicationas
irrelevanthypothesisappearsatleastasplausibleasanyoftheIatrogenichypothesesbasedonthedata.
Clinicaltrials
SeveralresearchgroupshavereportedmaniaasanadverseeventduringbothopenlabelandRCTsexaminingSSRIsas
treatmentforchildrenandadolescents.
Citalopram
Among174youthstreatedfordepressionwithcitalopramorplaceboinaRCT,nonedevelopedmania,althoughadverse
eventswerereportedspontaneouslyandmaniawasnotformallyassessed[80].Inanopenlabeltrialofcitalopram
treatmentforearlyonsetmajordepressivedisorder(MDD),ShiraziandAlaghbandRadfoundthatoverthe6weekstudy
period,16.7%ofchildrenandadolescentsexperiencedanunexpectedswitchtomania[81].Sincethedesignwasanopen
trial,itisparticularlyvulnerabletotheVigilanceissueandbecausethereisnocomparisongroup,thefindingsdonot
provideinformationregardingincreaseofrisk[28].
Escitalopram
Of264childrenandadolescentstreatedwithescitalopramorplacebofordepression,onedevelopedmaniahowever,this
occurredintheplacebocondition[82].Adverseeventreportingwasspontaneousorobservational.
Fluoxetine
PerhapsthebestknownstudyoffluoxetineforadolescentdepressionistheTreatmentofAdolescentDepression(TADS)
trial[30].TheTADStrialspecificallyassessedforthedevelopmentofmanicsymptoms.Fluoxetinewasgiveneither
aloneorincombinationwithcognitivebehavioraltherapy.Foursubjects(3.67%)onfluoxetinealoneandone(0.93%)in
thecombinationarmdevelopedsymptomsonthemaniaspectrumduringtreatment,versusoneonplaceboandnonein
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thecognitivebehavioraltherapyonlyarm.However,threeofthefivewhodevelopedmaniabeganthetrialwithhigh
baselinemaniasymptomscoresasassessedbytheAdolescentDepressionScale,developedspecificallyfortheTADS
trial.Atotalof38patientsoverallbeganfluoxetinetreatmentwithhighbaselinemaniascorestherefore,most(92%)of
patientsactuallytoleratedfluoxetinewellwithrespecttothedevelopmentofmaniaorhypomania.
Inanotherdoubleblind,randomized,placebocontrolledtrialoffluoxetinefordepressedchildrenandadolescents,6.25%
(n=3)ofyouthsreceivingfluoxetineexperiencedamanicepisodeduringtreatmentversusarateof2%(n=1)on
placebo[83].Inasecondrandomized,placebocontrolledtrialoffluoxetineforyouthswithdepression,oneparticipant
outof109developedamanicreactionwhilenoparticipantsintheplacebogroup(n=110)did.Thisdifferencewasnot
statisticallysignificant[3].Intherelapsepreventionphaseofthistrial,therewerenoreportsofmaniaamong20patients
remainingonfluoxetine,althoughwhetheritwasspecificallyassessedforwasnotstated[84].Go,MalleyandBirmaher
reportedthatduringopenlabelclinicaltreatment,30%of40youthswithobsessivecompulsivedisorder(OCD)and
mooddisordersdevelopedmanicorhypomanicsymptomswhentreatedwithfluoxetineorsertraline[59].Becausethe
studywasopenlabel,theVigilancehypothesisisamajorconcern.Owingtothecomorbidmooddisorders,theBipolar
depressionhypothesisisalsoviable.
Fluvoxamine
An8weekRCToffluvoxaminetreatmentforanxietydisorders,aswellasa6monthopenlabelfollowuptrialof128
participantsfromthe8weektrial,failedtoidentifyanyyouthsexperiencingmania[85,86].Neitherpublication
specificallystatesthattherewasnooccurrenceofmania,norisitclearwhatassessmentstrategy,ifany,wasusedto
assessforhypomaniaormania.
Paroxetine
InaRCTofparoxetinetreatmentfor206childrenandadolescentswithMDD,adverseeventswere'gatheredby
spontaneousreport',andnoincidentsofmaniawerereported[7].Thedevelopmentofmaniawasnotspecifically
assessed.
Sertraline
McConvilleandcolleaguesfoundthatoneoutofeighthospitalizedadolescentswithMDDdevelopedmaniaduring
openlabelsertralinetreatment[87].WagnerandcolleaguesconductedtwolargetrialsofsertralinetreatmentforMDDin
childrenandadolescentshowever,thesetrialsfailedtospecificallyassessformania,andnonewasreported[4].When
sertralinewasusedtotreatOCDin137childrenandadolescents,bothduringa12weekrandomizedplacebocontrolled
trial[88]andduringa52weekopenlabelextensionstudy[89],noneoftheparticipantsexperiencedmanicorhypomanic
symptoms.ThesefindingsareconsistentwiththeBipolardepressionhypothesisthe'switch'tomaniaappearswhen
peoplehavedepression,butnotwhentheyaretreatedwithantidepressantsforotherconditions(e.g.,attentiondeficit
hyperactivitydisorder)[79].Thepatternsuggeststhatitisthedepression,nottheantidepressant,thatappearsmore
linkedtothemania,aswasalsothecaseintheTADStrial(seeabove).
Venlafaxine
IntheTreatmentofSSRIResistantDepressioninAdolescents(TORDIA)trial,oneparticipantoutof83randomizedto
receivevenlafaxinedevelopedhypomania[31],assessedusingamaniascreenandtheManiaRatingScale.Inthesame
trial,noparticipantsdevelopedmaniaamong168randomizedtoreceivefluoxetine,paroxetineorcitalopramand83
randomizedtoreceivevenlafaxineincombinationwithcognitivebehavioraltherapy.
Theratesreportedhereformaniaasanadverseeventduringclinicaltrialsmayactuallyunderestimatethetruerisk,as
participantswithafamilyhistoryofbipolardisorderwereexcludedfrommostofthesestudies.Hadthesetrialsincluded
youthswithahigherriskofexperiencingmaniaevenintheabsenceofexposuretoantidepressanttreatment,ratesof
maniaduringSSRItreatmentmighthavebeenhigher.Ironically,therealsoappearstobeaconfound,wherethestudies
withstrongerdesigns(randomized,blindedandplacebocontrolledtrials)mayhavehadlessthoroughorsystematic
assessmentofmanicsymptoms,whereasopentrialsmayhavebeenmorevigilanttothepossibilityofmanicsymptoms.
ItisagainunclearwhetherSSRItreatmentcausedthemanic/hypomanicsymptoms,orwhetherthesemayhaveemerged
naturallyinthecourseofanexistingmooddisorder,buttheweightoftheevidenceappearstofavortheBipolar
depressionhpothesismorethananyoftheIatrogenichypotheses(ignition,scarorsideeffect).
Riskversusbenefitanalysis
TheEvidenceBasedMedicineframework[28]alsoprovideswaysofquantifyingthestrengthofassociationbetween
antidepressantsandmania.Theseincludetherelativerisk(RRtheratiooftheratesofmaniaintheantidepressant
exposedgroup,dividedbytherateinthenonantidepressantcomparisongroup),theoddsratio(oddsofmaniainthe
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antidepressantgroupdividedbyoddsofmaniainthecomparisongroup)andthenumberneededtoharm(NNH).The
NNHisthereciprocalofthedifferenceintheratesofmaniaintheantidepressantexposedversuscomparisongroup.
Conceptually,theNNHisthenumberofpatientsthatwouldneedtobeexposedtoantidepressantsbeforeonemoreon
averagewoulddevelopmania.TheNNHhasacorrespondingmeasureofthemagnitudeofbeneficialtreatmenteffects,
thenumberneededtotreat(NNT)inorderforonemorepatienttohaveagoodoutcome.TheNNTandNNHcanbe
combinedtocreatealikelihoodofhelpversusharm(LHHthereciprocalsoftheNNTdividedbythereciprocalofthe
NNH,sothatlargernumbersindicategreaterprobabilityofbenefit).
Whatwouldthesemetricssuggestabouttherelationshipbetweenantidepressantsandmania?Wefocusonfluoxetineas
anexample,because:first,fluoxetinehasthebestevidenceofefficacyforpediatricdepression[6]second,fluoxetine
appearstobeassociatedwithsomewhathigherratesofmaniathanotherSSRIs[90]andthird,fluoxetinehasmultiple
publishedRCTswheretheratesofmaniacanbecomparedwithratesinarandomlyassignedplaceboarm,providing
someofthebestevidenceavailableontheissue[3,59,83].PoolingtheresultsofthethreeRCTs,therateofmaniaon
fluoxetinewas2.8%,versusarateof1.0%onplacebo.TheRRofmaniais2.8,approachingtherangewhereweshould
beconcerned(RR3wouldbe'convincing')[28].TheNNHis56,meaningthatforevery56youthsexposedto
fluoxetine,onaverageonemorewoulddevelopmania.TheNNHestimatedseparatelyforeachRCTrangedfrom24to
145.Ontheotherhand,fluoxetineappearedefficaciousacrossallthreestudies,withNNTestimatesrangingfrom3.8to
6.5,andapooledestimateof4.7.TheLHHis11.8whenallthreestudiesarecombined,andrangedfrom6to22forthe
studiesseparately.Thus,whenfocusingonthecompoundwiththemostevidenceforefficacyandalsothegreatest
concernaboutmaniaasanadverseevent,patientsappearroughly12timesmorelikelytobenefitthantoexperience
maniaandeventheworstcasescenarioisthatpatientswouldstillbesixtimesmorelikelytobenefit.Estimatingthe
LHHseparatelyforseveralstudiesisonewayofconductinga'sensitivityanalysis',orexaminingtheextenttowhich
theLHHestimatechangesdependingonthestartingvalues.Sensitivityanalysescanalsoinclude'whatif'scenarios,
wheretheLHHisrecalculatedusingmoreliberalorconservativeestimatesofrisk,sothatthedecisionmakerscan
understandtheeffectsofchangingassumptionsonthefinalestimates[28].
ItispossibletofurthercustomizetheLHH,addingadditionalinformationaboutindividualfactorsaffectingthe
probabilityofriskorbenefit,aswellasincorporatingpatientpreferences.Strausetal.providedetailedexamplesof
addingthesefactorsintotheequation(seepage139143[28]).Onaverage,includingpatientpreferenceswilltypically
shiftthebalanceevenfurtherinfavorofbenefitinsteadofharm.Twomajorreasonsforthisaretheevidencethat
depressioncreatesmoreburdenthanmania,andhasaworseeffectonqualityoflife[91]andalsobecausedepressionis
themorelethalphaseoftheillness(includingbeingamajorcomponentofmixedstates)[44].Italsomaybepossibleto
shiftthebalancefurtherbyprovidingpsychoeducationtothefamily,usingcarefulmonitoringtodetectmania,and
establishingaplanformanagingmanicsymptomsshouldtheyemerge.Byincreasingtheknowledgeandtheexternal
supportsavailable,therisksassociatedwithmaniamaybemorecontained.Withclosemonitoring,itismorelikelythat
treatmentcouldbechangedduringhypomaniaratherthanwaitinguntilfullblownmaniamanifests.Atthesametime,the
irritablemoodandaggressionfrequentlyassociatedwithpediatricmaniaareoftenachiefconcernoffamiliesanda
majortreatmenttarget[92],sointerventionsthatincreasetheriskofdisinhibited,aggressivebehaviormayrequiremore
caution.
Limitations
Thereareseveralimportantlimitationstokeepinmind,bothaboutthestateoftheliterature,andalsoaboutthis
particularreview.Decisivestudiesabouttherelationshipbetweenantidepressantsandmaniahavenotbeenconducted,so
itisimpossibleforareviewtodrawdecisiveconclusions.Somelimitationsoftheliteratureinclude:
*Mostpublishedarticlesdonotsatisfymostofthecriteriaforprovidingavalidsourceofinformationaboutriskof
harm[28].Casereportsarenotadequate,unlessperhapstheyusedrechallenge,ABABdesigns,buttheseare
clinicallynotconducted.SeeBox1foralistoftheguidelinesandothercommentsonthestateoftheliterature
*Therearelargedifferencesintheratesofmaniaidentifiedacrossstudiesandinconsistenciesinthesizeofthe
findings,makingitplausiblethatmethodologicalissues(suchastheVigilanceorFalseAlarmhypotheses)orthenatural
courseofbipolardisorder(consistentwiththeMedicationasIrrelevantortheBipolarDepressionHypotheses)explain
thefindings,insteadofoneoftheproposediatrogenicmechanisms
*Therearemajordifferencesintheoperationaldefinitionofmaniaacrossstudies,andequallylargedifferencesinhow
maniaisassessedThesemakeitmuchmoredifficulttointerpretfindings
*Theremaybelocalandhistoricalchangesinpatternsofdiagnosis.Thesteepincreasesintherateofbipolardiagnoses
showsthattherehavebeendramaticchangesinpracticethatareindependentofchangesinactualrateofincidence.
Cliniciansmaybecomehypervigilanttothepossibilityofmania.Cognitiveheuristicsandpublicationbiasbothwilllead
tooveremphasizingthedegreeofrisk
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*Manychartreviewsandclinicaltrialsexcludedbipolaryouth.Wedonotknowratesofswitchingfortheseyouth
(versusyouthwithanxietyorMDDthathasnotyetshownitselftobebipolar)[cf.76],althoughtheadultliterature
suggestsitcouldbehigherthanwhatweareseeinghere.Conversely,studieswithyouthsexposedtoantidepressantswho
didnothaveahistoryofdepressionhaveconsistentlyfoundlowratesofmania[9395].Thetwocompetingexplanations
forthispatternoffindingsarethatassessmentofmaniainthesestudiesisnotsufficientlysystematictobesensitiveto
instancesthatactuallyareoccurring(avariantoftheVigilancehypothesis),orthatitispreviouslyundiagnosedbipolar
disorderthatwasbeingtreatedfordepression,andthensubsequentlymanifesteditsassociatedmanicsymptoms(the
Bipolardepressionhypothesis).Theinsufficientsensitivityargumentislessofaconcerngiventhatoneofthestudies
findingnoincreaseinriskwasasecondaryanalysisoflongitudinaldatafromoneoftheleadinginvestigationsof
pediatricbipolardisorder[79].
Anadditionallimitationofthisreviewisthatitdoesnotattempttometaanalyzetheexistingstudies,relyinginsteadon
qualitativewaysofappraisinganddescribingthefindings.Theliteraturedoesnotyetseemlargeenoughtosupporta
meaningfulmetaanalysis,particularlywithsofewstudiesreportingadequateinformationtoestimaterelativerisks.
Conclusions
Therehasbeenwidespreadconcernthatantidepressantsmightbeassociatedwithmania,bothatthelevelofindividual
casesandnowatthepublichealthlevel.Medicationexposureisoneofthepotentialfactorsunderdiscussionforthe
risingratesofpediatricmaniaintheUSA[24].Practitionerswantclearguidanceabouttheriskssothattheycanavoid
thepotentialharmoftriggeringmaniasinpatientswithdepression.Itisalsounclearwhetherantidepressantsshouldbein
thearmamentariumoftreatmentoptionsformanagingpediatricmooddisturbanceand,ifso,forwhichpatients.The
availableliteratureiscomplexandinconsistent,makingitdifficulttoformaneducatedopinionquickly.
Thisreviewattemptstomovebeyonda'boxscore'approachoftallyingthenumberofstudiesfindingevidencefor
antidepressantsinducingmaniaornot.Westartedbylayingoutsevendifferentmodelsofhowantidepressantscould
appeartobeassociatedwithmania.Threewerevariationsofiatrogenicmodels,whereantidepressantsmightigniteapre
existingdiathesisformania,createanewandlingeringriskformaniaorcreatemanicsymptomsasatemporaryside
effectofthecompound.Twoofthemodelspertaintothenaturalcourseoftheillness:onearguesthatmaniaoccurs
independentofthemedication,thatantidepressantsareirrelevant(orperhapsevenslightlyprotective).Thesecondbuilds
ontheNaturalcourseHypothesisbypointingoutthatcliniciansaremostlikelytoencounterbipolarillnessduringthe
depressedphase,thatthefirstphaserequiringtreatmentisalsooftendepressionandthatearlierageofonsetfor
depressionappearstobeassociatedwithbipolardisorder.Inshort,aconstellationoffactorsmayberesultingina
substantialportionofpediatricdepressionactuallybeingonthebipolarspectrum.Ironically,aconservativestanceabout
pediatricbipolardisordercouldresultinanunderestimationoftheriskfactorsandwarningsigns,leadingtoaninitial
underdiagnosisofbipolardisorderthatthenappearsto'switch'tomaniaasthepractitionerfollowsthepatient.The
finaltwomodelsaremethodologicalartifactsthatareoftencalled'confounds'.Skepticsoftenraisethepossibilitythat
pediatricbehavior'withinthenormallimits'ismistakenlypathologized.TheVigilancemodelholdsthatapparent
changesinratesofmaniaaredrivenbyshiftsinthesensitivityofclinicaldiagnoses.
Whatbecomesclearoverthecourseofthereviewisthattheiatrogenicmodelsarethemostprovocativeandthe
methodologicalartifactsaretheleastlikelytocommandattention.However,theweightoftheevidenceappearsto
suggestthatsomeoftheleaststirringordiscussedmodelsmayactuallyhavethemostsupport.Conversely,theiatrogenic
modelshavenotaccumulatedstrongevidencedespitethehighlevelofconcerntheyinviteandtheevidenceisweakest
intheRCTsthathavethestrongestdesigns.
Onthebasisofthisreview,theconclusionistoproceedwithcaution.BasedontheLHHframeworkfromEvidence
BasedMedicine,antidepressantsappeartoofferaclearnetbenefitfortheaveragepatient.TheEvidenceBasedMedicine
approachalsoofferspractitionersawayofcustomizingandpersonalizingclinicaldecisions,takingintoaccount
individualriskfactorsandpreferences.Thescaleswilltipfurtherinfavorofantidepressantusageincaseswherethe
depressionissevereorrefractory,andwheretherisksofmaniacanbecontainedbyprovidinggoodpsychoeducationto
thefamilyanddeployingcarefulassessmenttoolsthatwillbesensitivetotheemergenceofmaniaorsideeffects.In
caseswherethereisafamilyhistoryofbipolardisorder,orcaseswithahistoryofimpulsiveaggressivebehavior,then
thebalancewouldshiftawayfromSSRIusage(althoughtheevidenceofharmisnotmuchmorewellfoundedforthese
casesthanformaniaingeneral).
Futureperspective
Therearemanywaysthatthesituationwillimproveoverthenext5to10years.Theclinicalconcernthatantidepressants
mightinducemaniahasraisedawarenesstothepointthatfuturestudiesusingantidepressantsmaydothesystematic
assessmentofmanicsymptomsbothlifetimehistorypriortoenrollment,aswellaslookingforemergenceduring
treatmentneededtodecisivelyaddresstheissue.Improvedassessedtoolsarealreadyavailable(see[96]forreviewand
discussionaboutimplementation),andiftheyareadoptedmoreinresearchandclinicalpracticetherewillbeimmediate
improvementsinthemanagementofpediatricmooddisorder.Inthenearfuture,therewillbecontributionsfromthe
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personalizedmedicinevantagetoo,withimprovedassessmentintermsofgenotyping(includingidentificationof
individualdifferencesinresponsetomedication)[97],metabolicmeasuresofphysiologicalresponsetomedication,and
theuseofnoninvasivetechnologies(suchasactimetryorcellphonebasedlifecharting)toprovidemorerapidand
objectivemeasuresofmoodchange.Althoughtheissueofantidepressantsandmaniahasbeencomplexandcontentious
inthepast,researchisbeginningtomakecontributionstoevidencebasedtreatment,andthepacewillacceleraterapidly.
Box1.Criteriaforevaluatingwhetherevidenceaboutantidepressantinducedmaniaisvalid.
Criterion
Evaluationoftheliterature
1.Werethereclearlydefinedpatientgroupsthat
Nocomparisongroupincasestudies.Comparisongroupsdiffer
weresimilarinallwaysotherthanexposuretoan
acrossotherstudies.
antidepressant?
2.Weretreatmentsandmanicsymptomsmeasured
thesamewayinbothgroups?Wastheassessment
Openlabeltrialsandcasestudiesnotblinded.
ofmaniaobjectiveorblindedtoantidepressant
exposurestatus?
3a.Wasthefollowupperiodsufficientlylongfor
Variable,butoftensufficient(extendingouttoayearormore).
maniatooccur?
Strausetal.[28]offeraruleofthumbofignoringanystudywith
3b.Wasretentionadequate?Howweremissing
morethan20%losttofollowup,becausethiswilllikelyintroduce
datatreated?
bias.Missingdataareoftennotdiscussedinpublishedreportson
antidepressantsandmania.
4.Dotheresultssatisfysomeofthediagnostic
testsforantidepressantscausingmania?
4a.Isitclearthatantidepressantexposure
Ifassessmentofmaniaisnotrigorousatbaseline,thenprior
precededtheonsetoftheoutcome?
hypomaniacanescapedetection.
Doseresponsehasnotbeendemonstratedforantidepressant
4b.Isthereadoseresponsegradient?
inductionofmaniayet.
Wehavenotfoundarechallengestudyintheliterature.Thereisa
4c.Isthereanypositiveevidencefroma
withdrawalrechallengestudy?
blindedwithdrawalstudy[98].
4d.Istheassociationbetweenantidepressantsand No.Resultsrunthefullgamutfromincreasedratesofmania,tono
maniaconsistentfromstudytostudy?
differenceinrates,tosignificantdecreasesinratesofmania.
4e.Doestheassociationbetweenantidepressants
Yes,clearly.
andmaniamakebiologicalsense?
Adaptedfrom[28].
Executivesummary
Background
*Thedecisivestudytoestablishtheriskofanantidepressanthasnotbeenconducted.Thiswouldrequireadouble
blinded,placebocontrolledtrialwithexcellentassessmentofmanicsymptoms,includingalifetimehistorypriorto
randomization,andalongenoughfollowuptocapturethemajorityofsubsequentmanicevents.
*Antidepressantinducedmaniainadultsisagenerallyacceptedclinicalphenomenon,evenintheabsenceofsucha
decisivestudy.
*Theexistingliteratureregardingpediatricantidepressantusageandmaniaisalmostentirelybasedondesignsproneto
bias.
Modelsoftherelationshipbetweenantidepressants&mania(&sevenpotentialpitfalls&remediesfor
practitioners)
*Ignitionhypothesisuncoveringalatentdiathesis,turningongenesthatwerealreadypresent.Althoughofgreat
concern,thereislittlesupportingevidenceforthisfromstudieswithstrongerresearchdesigns.
*Scarhypothesiscreatinganewdiathesisintheabsenceofpriorbiologicalrisk.Thisisperhapsthemostworrisome
hypothesis,andalsooneofthemostspeculative,withnodirectsupportingevidenceyetintheliterature.
*Sideeffecthypothesistemporarydeleteriouseffectofdrug,butnotatruemanifestationofabipolarillness.This
hypothesisappearstobeplausible,buttheeffectsappeartoberareinstudieswithstrongdesigns.
*Vigilancehypothesisincreasedmonitoringfortheillness,butnoactualchangeinrisk.Thishypothesisislikelyto
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contributetothehighratesofmaniaobservedinopentrials,whichironicallyoftenhaveusedbettermonitoringofmanic
symptomsthanmanyoftheblinded,randomized,controlledtrials.
*Medicationasirrelevanthypothesiswhatwearewitnessingisthenaturalcourseofthebipolarillness,nota
responsetothetreatment.Thishypothesisappearsconsistentwithlongitudinaldataaboutcourseofillnessand
epidemiologicaldataitcanalsoaccountformuchoftheapparentlyhighrateofmanicsymptomsemergingduringthe
courseoftreatmentformooddisorders.
*Falsealarmshypothesismislabelingjuvenilebehavioraspathologicalwhenitstillfallswithinnormallimits
mistakingirritabilityduetoothercausesasanindicatorofpediatricmaniaoralternately,mistakingthereturnofenergy
andpositiveemotionsasdepressionliftsforhypomania.Thisisalsoaplausiblehypothesis,especiallygivenemerging
evidenceoflargedifferencesindiagnosticformulationsforsimilarsymptompresentationsacrosspractitioners,clinics
andevencountries.
*Bipolardepressionhypothesiswhentreatingyouthsfordepression,weareoftendealingwiththedepressedphase
ofwhatwillprovetobeabipolarillness.Thisappearstobealikelycontributortotheratesofmanianotedduring
treatmentofmood,andactuallycouldexplainseeminglyhigherratesinyouthsthanadultsbecauseofthepossibilitythat
bipolardepressionwillbethefirstphaseofillnesstodrivetreatmentseeking.
Reviewoftheevidenceforantidepressantspotentiallyinducingmania
*Casestudiesofselectiveserotoninreuptakeinhibitor(SSRI)inducedmaniainyouthsarecommon,butaddlittle
evidenceabouthowpatientsshouldbetreated.Casestudiesarebiased'youthonantidepressantsfailstobecome
manic'isunlikelytobepublished.
*PublishedchartreviewstudiesofSSRIcoincidentmaniagenerallyfailtomeetguidelinesfordemonstratingclear
evidenceofharm.
*Clinicaltrialsexistformostoftheantidepressantsusedwithyouthshowever,theassessmentandreportingofmanic
symptomswasnotrigorousinolderstudies.Thiscouldleadtounderestimatingabsoluteratesofmania,butshouldnot
biasestimatesofrelativeriskforantidepressantsversusplacebo.
Riskversusbenefitanalysis
*Depressionisworsethanmaniaintermsofburdenontheindividualandriskofsuicide.Thegreaterriskandburden
maytipthescaleinfavorofcontinuingtouseantidepressantstomanagethedepression,withclosemonitoringformania.
*Fluoxetinehasthebestcurrentdataabouttreatmentefficacy,andalsosomeofthegreatestconcernsaboutpotential
associatedmania.Basedonthreerandomizedtrials,thelikelihoodofhelpversusharm(mania)onfluoxetineismore
than11,favoringantidepressantuse,beforeconsideringpatientcharacteristicsorpreferences.
Limitations
*Decisivestudieshavenotbeencarriedout.Theliteraturedoesnotsupportaclear'finalanswer'aboutthe
relationshipbetweenantidepressantsandmania.
Conclusions
*Proceedwithcaution.Despitethegreatconcernaboutthepossibilityofantidepressantsincreasingtheriskofmania,
thestudieswiththestrongestresearchdesignsfindthesmallestevidenceofrisk.
*Patientsonfluoxetinearemorethantentimesmorelikelytobenefitthanexperiencemania.Takingpatient
preferencesintoaccountwilloftentipscalesfurthertowardsantidepressantusagetomanagemood.
*Educationaboutmedicationandsideeffectsandcarefulmonitoringformaniawillfurthercontainrisks.
Futureperspective
*Personalizedapproachestomedicine,includinggeneticandmetabolictestingaswellastechnologicalimprovements
inassessmentofmoodandenergy,willsoonprovidepowerfultoolstohelpgaugeriskandresponsetoantidepressantsas
wellasothertreatmentregimens.
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AuthorAffiliation(s):
1UniversityofNorthCarolinaChapelHill,DepartmentofPsychology,CB#3270,DavieHall,ChapelHill,NC

27599,USA.megan.joseph@unc.edu
2UniversityofNorthCarolinaChapelHill,DepartmentofPsychology,CB#3270,DavieHall,ChapelHill,NC

27599,USA.eay@unc.edu
3UniversityofNorthCarolinaChapelHillSchoolofMedicine,DepartmentofPsychiatry,CB#7160,10612

NeurosciencesHospital,101ManningDrive,ChapelHill,NC27599,USA.jair_soares@med.unc.edu
AuthorNote(s):
[dagger]Authorforcorrespondence
Financial&competinginterestsdisclosure
ThisresearchwaspartlysupportedbyNIHR01MH69774(Soares),RR20571(Soares),aswellasNIHR01MH066647
(Youngstrom).MeganFJoseph,MA,andEricAYoungstrom,PhD,havenofinancialrelationshipswithany
pharmaceuticalcompany.JairSoares,MD,isonthespeaker'sbureauatEliLillyandAstraZeneca,isaconsultantfor
OrganonandShire,andreceivesgrantfundingfromPfizerandGlaxoSmithKline.Theauthorshavenootherrelevant
affiliationsorfinancialinvolvementwithanyorganizationorentitywithafinancialinterestinorfinancialconflictwith
thesubjectmatterormaterialsdiscussedinthemanuscriptapartfromthosedisclosed.
Nowritingassistancewasutilizedintheproductionofthismanuscript.
MeganFJoseph,EricAYoungstrom,JairCSoares
SourceCitation(MLA7thEdition)
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Joseph,MeganF,JairCSoares,andEricAYoungstrom."Antidepressantcoincidentmaniainchildrenandadolescents
treatedwithselectiveserotoninreuptakeinhibitors."FutureNeurology4.1(2009):87+.AcademicOneFile.Web.26
Apr.2015.
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