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Title:AntidepressantcoincidentmaniainchildrenandadolescentstreatedwithselectiveserotoninreuptakeinhibitorsAuthor(s):MeganFJoseph,JairCSoaresandEricAYoungstromSource:FutureNeurology.4.1(Jan.2009):p87.DocumentType:ReportDOI:http://dx.doi.org.vlib.interchange.at/10.2217/14796708.4.1.87Copyright:COPYRIGHT2009FutureMedicineLtd.http://www.futuremedicine.com/loi/fnlFullText:

Author(s):MeganFJoseph1,EricAYoungstrom[[dagger]]2,JairCSoares3

Keywords

adolescentsantidepressantchildrencitalopramfluoxetineinducedhypomaniainducedmaniaparoxetinesertralineSSRIswitchvenlafaxineyouth

Theincreasinguseofselectiveserotoninreuptakeinhibitors(SSRIs)totreatchildrenandadolescentswithpsychiatricdisordershascausedconsiderablecontroversy[1].Theuseofantidepressantsinyouthstripledbetween1987and1996,withratesofprescriptionrisingfromthreeper1000totenper1000childrenandteenagersand21per1000youthsinthe1518yearoldrange[2].AlthoughsomeSSRIshavedemonstratedefficacyundercontrolledconditionsinrandomizedclinicaltrials[3,4],thereisevidencethatmanyofthesedrugsmaynotbeefficaciousingeneralclinicalsettings[57].Thepotentialbenefitofantidepressanttreatmentneedstobeweighedagainstthepotentialcostsandriskswhendecidingwhethertoprescribe[8].PerhapsthemostsalientconcernisthedebateoverwhetherSSRIscausesuicidalideationorbehaviorinadolescents[9].Althoughtherelativeriskofsuicidewhentakingantidepressantsissmall,suicideissuchaseriousoutcomethatthishasledtotheUKrestrictingtheuseofantidepressantsinchildrentofluoxetineincombinationwithcognitivebehavioraltherapy[10].AnadditionalpointofconcernthathasreceivedlessattentionintheliteratureisthequestionofwhetherSSRIsmayinducemaniaorhypomaniainchildrenandadolescents.Currentevidencesuggeststhatthisisatopicworthyoffurtherempiricalstudy[11],aswellasoneofsignificantclinicalconcern[12,13].Althoughmaniaisalesssevereoutcomethansuicide,itmaybeamuchmorecommonadverseevent,suggestingthatthepublichealthburdencouldbesimilar.

Thereareimportantreasonstofocusonreviewingtherelationshipofantidepressantsandmaniainyouths.AlthoughthereisasubstantialbodyofliteraturesuggestingthatantidepressanttreatmentwithSSRIscancauseanaffectiveswitchtomaniaorhypomaniainadults[1417],comparativelylittleisknownaboutthisphenomenoninchildrenandadolescents.Importantly,epidemiologicalevidencesuggeststhatthereisanegativecorrelationbetweenageandriskforantidepressantinducedmania[18].Putanotherway,theriskofinducingmaniawithantidepressantmedicationmaybeespeciallyhighforchildrenandadolescents14yearsoldandyounger[19].Youngerageatfirsttreatmentforbipolardisorderhasalsobeenreportedasapredictorofvulnerabilitytoantidepressantinducedcycleacceleration[20].

Severalfactorsmakeitchallengingtodrawfirmconclusionsbasedontheliteratureregardingantidepressantsandmania.Oneisthemethodologicalshortcomingsoftheliterature.Thedecisivedesigntoevaluatetheriskofantidepressantinducedmaniawouldbetotakeagroupofyouths,randomlyassignhalftoantidepressantsandhalftoplaceboandthenfollowthemoveralongtimeperiodtoevaluatetherelativeriskofdevelopingmaniawhiletakingantidepressants.Unfortunately,theavailablestudiesusingrandomandblindedassignmenthavenotusedstateoftheartassessmentformanicsymptoms,andthestudieswithbetterassessmenthaveusednonexperimentaldesigns.Additionally,severallimitationsprecludeusinglongitudinalrandomizedcontrolledtrial(RCT)designstoexaminethisissue,includingneedingaverylarge(ifnotprohibitive)samplesizeforadequatepowerandthepotentialethicaldilemmaofrandomizingadolescentstonoantidepressantsforalengthyperiodoftimewhensomebelievetheyareaneffectivetreatment.Asecondissueisthecomplexityofthepossiblerelationshipsbetweenantidepressantsandmania.Mostarticleshavenotdefinedaprioriconceptualmodelsortestedcompetingmodelsagainsttheevidence.Thisreviewwilldelineatesevendifferentconceptualmodelsthreeofwhichinvolveantidepressantshavinganiatrogeniceffect,twopertainingtothenatureofbipolardisorderandtwothataredrivenbyartifactsoftheassessmentprocess.Athirdissueisthat,intheabsenceofdecisivedataandanalyses,thepopularityofexplanationsandthechoicesmadebypractitionersaregoingtobedrivenbyfactorsbesidesevidence.Intheparlanceofthedecisionmakingliterature,weareforcedtorelyonheuristicstoguideourpractices,andthesemaybebiasedinpredictablewayssuchasoverestimatingrisks[21].

Thisreviewattemptstoaddressthethreechallengesby:

*RelyingonexplicitcriteriafromEvidenceBasedMedicine[28]forevaluatingthequalityofthestudiesprovidingevidenceaboutthepotentialassociationbetweenantidepressantsandmania

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*Providingspecificconceptualmodelsoftherelationshipthatincludepotentialconfoundsaswellasharmfuleffectsofmedicationaspossibleexplanations

*Qualitativelyevaluatingtheevidencewithregardtoeachmodel

*Qualitativelydescribingtheprovocativenessofeachmodelorthedegreetowhichitmightcaptureattentioninbothclinicalandpopularaudiencesforreasonsbesidessupportingevidence

*Illustratingaquantitativeapproachforweighingthelikelihoodofhelpversusharm(LHH),againborrowedfromEvidenceBasedMedicine[28].

Thereviewcloseswithrecommendationsaboutimprovedassessmentstrategiesthatcanhelpmanagetheriskofmaniaduringtreatmentofdepression,aswellasinformingfutureresearchinthisarea.

Modelsoftherelationshipbetweenantidepressants&mania(&sevenpotentialpitfalls&remediesforpractitioners)

Thefollowingsectiondescribessevendifferentconceptualmodelsofthepossiblerelationshipbetweenantidepressantmedicationsandmanicsymptoms.Foreachmodel,thereisastatementaboutthepotentialassociatedpitfallsfromthevantageofthepractitioner,alongwithstrategiestoavoidoramelioratethepitfall.Eachmodelisalsoratedintermsofits'provocativeness',conveyingthedegreetowhichthemodelislikelytogainattentionowingtofactorsbesidesjusttheweightofevidencesupportingit.More'provocative'modelsarelikelytoplayuponfearofcausingharm(cognitivesciencehasdemonstratedthathumanbeingsgivegreaterweighttopotentialrisksthanbenefitsindecisionmaking)orasenseofscandal.Moreprovocativemodelswouldbeofconcerntopractitionersandwouldalsoreadilyattracttheattentionofmediaoutletsthatareperhapsfirstconcernedwithpopularappealabovescientificevidence.Conversely,lessprovocativemodelsmayhaveamoredifficulttimecapturingimaginationsandgainingbroaddissemination,eveniftheyhappentobeaccurate.Next,weevaluatethedegreetowhichthemodelinquestionissupportedbytheavailableevidence.Theratingsattachedtotheprovocativenessand'likelihood'obviouslyincludealargedegreeofsubjectivity.Wedonotpretendthattheyarecompletelyobjectiveorpreciseanddidnotrelyonformalcodingcriteria,butweintendthemtobeaconciseandclearwayofcommunicatingourimpressionsbasedonaqualitativereviewoftheliterature.Wealsowanttobeclearthattheterm'likelihood'isnotintendedtoconnoteanyformalstatementaboutprobability(i.e.,ascoreof6doesnotmeanthatthereisa6/7chancethatthetheoryiscorrect).Finally,wepresentsomepotentialresearchdesignsthatcouldmoreinformativelytesteachofthedifferentmodels.

Ignitionhypothesis

Uncoveringalatentdiathesis,turningongenesthatwerealreadypresent.Thetinderofbiologicalandenvironmentalriskfactorswerealreadypresentandtheexposuretothemedicationprovidedthesparknecessarytolightthebipolar'blaze'.TherehasbeenadramaticincreaseintherateofdiagnosisofbipolardisorderintheUSA[22,23],leadingtospeculationthatthehigherratesmay,inpart,beattributabletothehigherrateofmedicationprescriptionintheUSAignitingalargeramountofmaniainthepopulation[24].Potentialpitfall:selectinganagentthatisalogicalchoiceforthepresentingsymptomsbutdestabilizesthepatient.Remedy:carefulassessmentofriskfactors,carefulmonitoringofpossibleswitchorbreakthroughmaniaandrapidchangeinpharmacologyaftermanicsymptomsemerge.Provocativeness(17,with7beingthemostprovocative):5.TheIgnitionhypothesisisthescenariomostwidelydiscussedatmeetingsandinthepopularpressisthereasubsetofpatients(thosewithbipolardisorder)whoactuallyarelikelytobeharmedbyfrontlinetreatmentsfordepression?EuropeanregulatoryagenciesandothergroupsareconcernedthatthehigherratesofpediatricmaniaintheUSAmaybeatleastpartiallyattributabletothehighratesofexposuretomedication[24].Likelihoodbasedonavailableevidence:4.Informativewaytoevaluate:demonstrategenecompoundinteractions.Thishasnotyetbeendoneinpsychiatry,butcouldbeaccomplishedbyaddinggenotypingtoPhaseIIItrials,orbypersonalizedmedicinedataminingapproaches(comparingthegenomeagainsttreatmentadverseeffects).Forexample,workinTypeIIdiabeteshasrevealedgeneticpolymorphismsassociatedwithedema,orfluidretention,asideeffectofdrugtreatment[25].Studiessuchasthesefrombranchesofmedicineotherthanpsychiatrysuggestthatlinkinggeneticinformationwithmedicationsideeffectsispossible.However,duetolowbaseratesofmaniaasasideeffect,theseapproacheswouldrequirehugesamplesizes,thoughthesearebeingbuiltrapidly,andalsomoresystematiccodingofmanicsymptomsthanistypicallydone.Ideally,anypharmacogeneticresearchinthisareawouldalsotakeintoaccountenvironmentalfactorshowever,thisisdifficultonalargescaleandexamininggenebymedicationinteractionsmaybemorefeasible.

Scarhypothesis

Creatinganewdiathesisintheabsenceofpriorbiologicalrisk.Potentialpitfall:causingharmwithwellintentionedandlogicaltreatmentfordepression.Remedy:carefulassessmentofriskfactors,intensemonitoringtodetectemergentmania,andarapidswitchinpharmacology.Provocativeness:7.Thisisthescarymonsterlurkingintheclosetforprescribers.Takeonebrain,previouslyincapableofdevelopingmania,treatitfordepressionandleaveitpermanently

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vulnerabletomanicepisodes.Likelihoodbasedonavailableevidence:2.Therearenodecisivestudiesrefutingthispossibility.However,therearemanyotherscenariosthatappearmuchmoreplausible,bothascausesofmanicsymptomsandalsobecausetheideathatbriefexposuretoacompoundcouldproducepermanentdeleteriouschangecontradictsgrowingknowledgeoftheplasticityoftheCNSanditstendencytosurviveandrecoverfrominsult.Informativewaytoevaluate:demonstratechangesinbrainmorphologyorpathophysiologyfollowingmedicationexposure,andshowthatthesepredictrecurrencesofmania.Itwouldbedecisiveifitcouldbedemonstratedthatthesechangesoccurafterexposuretothecompoundevenintheabsenceofestablishedgeneticriskfactorsforbipolardisorder.

Sideeffecthypothesis

Temporarydeleteriouseffectofthedrug,butnotatruemanifestationofabipolarillness.Potentialpitfall:theerrorwouldbeinattributingthesymptomstoadiseaseinsteadoftheimperfectdrug.Remedy:avoidlabelingpeoplewithmanicsymptomsoccurringwhiletakingantidepressantsashaving'bipolardisorder'.Atpresent,theDiagnosticandStatisticalManualofMentalDisordersIVTextRevision(DSMIVTR)indicatesthattheseeventsshouldbecodedas'substanceinducedmania'ratherthanaformofbipolardisorder[26]becauseofthepossibilitythatthesymptomsareasideeffectratherthananunmaskingofabipolardiathesis.Theclinicalmanagementtypicallywouldinvolvechangingpharmacotherapyandusingintensiveassessmenttoevaluatewhethermoodsymptomspersistataproblematiclevel.Provocativeness:3.TheSideeffectargumentmotivatedsomehighprofilelawsuitsbackwhencompoundswerefirstintroduced,butthisscenariohasdefinitelybeeneclipsedbytheIgnitionandScarhypothesesinrecentdiscussions.The'sideeffect'modelislessfrighteningbecauseitpositsthattheharmfuleffectsofthecompoundarelimitedinduration(orelseittransformsintotheScarHypothesis).Likelihoodbasedonavailableevidence:4.Informativewaytoevaluate:ABABdesign,alsoknownasachallengewithdrawalrechallengestudy,todemonstratethatsideeffectsonlyhappenwhenexposedtotheagent.TheSideeffecthypothesiswouldalsobesubstantiatedbyeithershowingthatmanicsymptomsoccurintheabsenceofgeneticriskforbipolardisorder,orbyshowingthatthepathophysiologyofsideeffectsisdifferentfromthepathophysiologyofbipolardisorder.

Vigilancehypothesis

Increasedmonitoringfortheillness,butnoactualchangeinrisk.TheVigilancehypothesisisavariantof'verificationbias',whichplaguesmedicalassessmentandrepresentsaseriousthreattothevalidityofanystudieswithoutblindedevaluationandastringentlydefinedcomparisongroup(ideallybasedonrandomassignment)[27,28].Potentialpitfall:confusingheightenedmonitoringwithincreasedrisk.Fallingvictimtoacognitiveheuristicandrememberingthecaseswheremaniaoccurred,butdiscountingthecaseswhereitdidnotoccurwhileusingantidepressants.Remedy:evaluateallpatientsonantidepressantsforpossibleemergenceofmanicsymptomsavoid'workup'bias.TheUSFDAnowrecommendsevaluationforpossiblebipolardisorderwhenprescribingantidepressantmedications,althoughthesuggestedlanguagecurrentlyfallsshortofa'blackbox'warning[101].PractitionerscanfindreviewarticlesandRCTsandlearnriskratesfromthem.Provocativeness:1.Thereisvirtuallynothingexcitingorglamorousaboutthevigilancescenario,anditisunpopulartoberemindedthatweareimperfectatweighingandcombininginformation[29].Likelihoodbasedonavailableevidence:5.Aswewillsee,studieswithstrongerdesignstendtofindlowerratesoftreatmentemergentmania.Additionalargumentsinfavorofthispossibilityare:first,theinaccuracyofmanyclinicaldiagnosesofbipolardisordersecond,theinadequacyofmanyclinicalevaluationsintermsofascertainingfamilyhistoryorpriorhistoryofhypomania[cf.30,31]andthird,thefailureofmostclinicianstoconsiderbipolardisorderasapossibilityinyouthsuntilrecently,andthewidelyunevenimplementationofconsistent,evidencebasedpracticesaroundthecountry,evenatpresent.Informativewaytoevaluate:researchstudyconductingsameintensityoffollowupforthoseexposedtoantidepressantsversusothercompounds,orsystematicallyvaryingtheintensityoffollowupforthesameantidepressantmedication.Presentingclinicianswithcasevignetteswherethecontextinwhichsymptomsarepresentedisvariedcouldalsobeinformative.Ideally,userandomassignmentandalargetrialtoequategroupsoncharacteristicsbesidescompound.

Medicationasirrelevanthypothesis

Whatwearewitnessingisthenaturalcourseofthebipolarillness,notaresponsetothetreatment.The'naturalcourse'confoundiswidelyrecognizedasarivalhypothesisinmethodologycirclesthatpotentiallyaffectsanydesignexceptforarandomizedtrial[32,33].Inthecaseofbipolardisorder,thepossibilitythatchangesinmoodareduetothenaturalcourseoftheillnessisnotavagueacademicpremiseitisawelldocumentedclinicalphenomenon.Potentialpitfall:blamingatreatmentforaneventthatwascompletelyunrelated.Remedy:findandrelyonwelldesignedresearchaboutriskstoavoidheuristicsandclinicalillusionsaboutclinicalphenomena.Provocativeness:1.Thereisnoelementofintrigue,noblametobeassignedtothecompoundorthepractitioner,exceptperhapsfailingtorecognizethe'greatmasquerade'ofmentalillnessinitsfirstguises.Likelihoodbasedonavailableevidence:6.Informativewaytoevaluate:combinestudieslookingatantidepressantcoincidentmania(ACM)incaseswithbipolardisorderrandomizedtoeitherantidepressantorplacebo(realistically,bothasadjuncttoanothermoodstabilizingcompound)thiswouldhelpruleoutacausalroleofthecompound.Goodepidemiologicalandnaturalhistorystudiesarealsoneededtounderstandratesofhypomania(sorelylackinginepidemiologicalstudies)andratesofrecurrence[cf.34].

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Falsealarmshypothesis

Mislabelingjuvenilebehavioraspathologicalwhenitstillfallswithinnormallimitsmistakingaggressivebehaviorduetoothercausesaspediatricmania[35]oralternatively,mistakingthereturnofenergyandpositiveemotionsasdepressionliftsforhypomania.Potentialpitfall:attributingbehaviortoadiseasethatisnotpresent.Remedy:useassessmenttoolsthatextendbeyondtheroutineclinicalinterview,especiallytoolsthatrelyonagenormsordirectcomparisonstootherclinicalsamples.Adopt'probabilityofdiagnosis'approachfromEvidenceBasedMedicinetoacknowledgewhencasesareambiguousinsteadofclearcut[28].Provocativeness:6,ifyouareskepticalaboutthediagnosisofpediatricbipolardisorder2ifclinicallyactiveinthearea.TheFalsealarmhypothesisappealstothosereadytojumponthe'pathologizingchildhood'bandwagon[36],aswellasplayinguponconcernsabouttheoverdiagnosisofbipolardisorder[36].Thosewhoworkinclinicalsettingsorconductresearchwiththeseyouthsencountersevereenoughimpairmenttomakethe'justbeingakid'explanationimplausibleinmostcases.Likelihoodbasedonavailableevidence:2.Informativewaytoevaluate:muchworkhasbeendonevalidatingtheconstructofpediatricbipolardisorder[3739].Basedonthevaliditydata,itisclearthatatleastsomecasesofmaniareflectanunderlyingbipolarillness.Conversely,therearedefinitelycasesthatarelabeledandtreatedas'bipolar'whenitisacompletelydifferentprocessleadingtothesymptoms.Carefulindividualassessmentisthebestwayforward.

Bipolardepressionhypothesis

Earlyonsetdepressionisariskfactorforbipolardisorder[4042],andmanypeoplewithbipolardisorderfirstseektreatmentduringadepressedepisode[43,44].Thesefindingssuggestthatwhentreatingyouthsfordepression,weareoftendealingwiththedepressedphaseofwhatwillprovetobeabipolarillness.Potentialpitfall:blamingtreatmentforthenaturalcourseoftheillnessfailingtorecognizebipolardepression.Remedy:assessment,againcarefullyevaluatefamilyhistoryofbipolardisorder,assessforpriorhypomaniasormaniasassessformixedstates.Provocativeness:5.Theappealwouldcomefromthestealthfactor,thattheillnesshasbeenavoidingdetectionpreviously(contradictingcurrentconcernsaboutoverdiagnosisofbipolardisorder).Likelihoodbasedonavailableevidence:6.Informativewaytoevaluate:attheresearchlevel,studiesareneededthatcarefullyfollowchildrenandteenagerswithdepressionprospectively,tofindhowmanyofthemdevelophypomaniaormania.Thenextgenerationofresearchneedstoincorporatestrategiestoaccuratelydetecthypomania,whichhasbeentheAchillesheelofpriorresearch,leadingtotheambiguitiesforbipolarIIandcyclothymicdisorder.Asimilardegreeofsophisticationabouthypomaniaalsoneedstobedeployedinclinicaltrialsofantidepressants,especiallyplacebocontrolledstudies.

Guidelinesforevaluatingstudiesofharm

TherehasbeenamovewithinthefieldofEvidenceBasedMedicinetodevelopasetofguidelinesorcriteriaforevaluatingstudiesquickly,gaugingtheirdesignandappraisingtheirvalidityandrelevanceforindividualpatients.TheseincludetheConsolidatedStandardsofReportingTrials(CONSORT)criteria[32]forclinicaltrials,aswellasaseriesofbriefarticlesthatappearedasaseriesinJAMAbeforebeinganthologizedandexpanded[45].Perhapsthemostaccessiblediscussionoftheseguidelinesandtheirapplicationtoindividualcasesisofferedinthebook,'EvidenceBasedMedicine'[28].Ifantidepressantsdoinfactincreasetheriskofmania,itwouldbeanexampleoftreatmentcausingharm.Box1providesasetofcriteriaforevaluatingwhethertheevidenceaboutantidepressantscausingharminotherwords,inducingmaniaisvalid(adapted[28]).Wewillrefertothesecriteriawhenevaluatingthepublishedstudies.

Reviewoftheevidenceforantidepressantspotentiallyinducingmania

Antidepressantinducedmaniainadults

Antidepressantinducedmaniaisawellknownclinicalphenomenoninadults[14,15].Metaanalysissuggeststhatapproximately3.7%ofindividualswithunipolardepressionmayexperienceaswitchtomaniafollowingexposuretoaSSRI[46],while2444%ofindividualswithbipolardisordermayexperienceanaffectiveswitchwhiletakinganSSRI[17,47].Importantly,adults(andchildren)withbipolardisordertypicallyspendalargerpercentageoftimedepressedthanmanic/hypomanic[48,49],suggestingthattreatmentofdepressionmaybethemostimportantaspectofpsychopharmacologicalmanagementofbipolardisorder[11,50,51].

ManiacoincidentwithSSRIusageinyouths

ThenextportionofthereviewconcentratesontheliteraturepertainingtomaniaandSSRIsinyouths.WefocusedonSSRIsbecausetherelativelybenignsideeffectprofilehasmadethemalmostuniversallypreferredtothecyclicantidepressantsandmonoamineoxidaseinhibitorsinpediatricsamples[2,52].MedlineandPsycInfoweresearchedusingtheterms'childrenoradolescentsoryouth','mania','SSRI','inducedmania'and'antidepressantinducedmania'.Additionalreferencesweregatheredfromthereferencelistofidentifiedarticles.Thissearchstrategyidentified

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36articlesforthereview.

CasestudiesofpediatricmaniacoincidentwithSSRIusage

TherearemanycasestudiesdescribingantidepressantinducedmaniainchildrenandadolescentstreatedwithSSRIs,includingcitalopram(fivecases)[53,54]fluoxetine(11cases)[5559]paroxetine(sevencases)[6063]sertraline(fivecases)[6467]andvenlafaxine(aserotoninnorepinephrinereuptakeinhibitoronecase)[69].Thesereportsdescribeayoungpersontreatedforanxietyordepression(andinonecase,epilepsy)[53],whodevelopedsymptomsofmaniaorhypomaniaaftertreatmentwithanSSRIforperiodsoftimethatweretypicallyshort(8weeksorfewer)[54,5662,6466]

,butweresometimeslong(from5monthstoayear)[53,57,58,63].Themediantimetoonsetofmaniawas21days,witharangefrom2to365days.Theseindividualsvariedintermsoffamilyhistory.Atotalof21%hadafirstdegreeorotherrelativewithdiagnosedbipolardisorder45%didnothaveafamilyhistoryofmooddisorders.

Theonsetofmania/hypomaniausuallyfollowedthecommencementoftheSSRI,butinsomecasesitwastheresultofanincreaseindoseafterthepatienttoleratedlowerdoses.Cessationofantidepressanttreatmentledtoaresolutionofthemanic/hypomanicsymptomsin59%ofcases,whileamoodstabilizerwasusedin38%ofthecasesinordertomitigatesymptoms[5355,57,59,62,65,67,68].Nearlyallcasestudiesreportedthatfollowingthecessationofthemanicsymptoms,thepatientthenremained'stable',typicallyoffoftheantidepressantorsometimesatalowerdosethepatientmayhavecontinuedonamoodstabilizerifonehadbeenadded.However,theperiodoftimeforwhichtheywerefollowedvariedamedianof20weekswitharangefrom2to52weeks.

Takenasawhole,thesecasestudieswouldseemtosuggestthatcautioniswarrantedwhentreatingchildrenandadolescentswithSSRIs,astherearedocumentedcasesofthistreatmentcoincidingwithmaniaorhypomania.However,itisalsoimportanttokeepinmindthatmooddisordersshownaturalfluctuations(withthe'Medicationasirrelevant'hypothesisrepresentingtheextremeviewthatwhatappearstobetreatmentemergentmaniaisactuallyjustabipolarillnessfollowingitsownnaturalcourse,independentofthepresenceorabsenceofantidepressantmedication),andthereforecausallinkstothedevelopmentofmanicsymptomsbytheadditionofanSSRI,orresolutionofmanicsymptomsbyremovaloftheSSRI,cannotbeestablishedbycasestudies.ThepharmacokineticsofantidepressantmedicationsmaketheuseofABABdesigns,whichcanbehelpfultoolsforestablishingcausalityorefficacyattheindividuallevel,difficultowingtothelonghalflivesandresultinglengthoftimeneededtotitrateorwashoutmedication.Additionally,casestudiesareprobablyabiasedsourceofinformation,astheyarewrittenaboutpatientswhostandoutintheclinician'smind.ReportsofyouthstreatedwithSSRIswhodonotdevelopmaniadonotappearintheresearchliteratureascasestudies.Thesameheuristicmayalsooperateattheleveloftheindividualclinician:itismuchmorememorablewhenacaseshowsanadverseeventsuchasmaniaversusacasethatdoesnotandhumansasdecisionmakersarepronetogivingmuchgreaterweighttonegativeeventsasanevolvedheuristicforavoidingrisks[69].

ChartreviewstudiesofSSRIinducedmania

SeveralchartorcasereviewshaveattemptedtoexaminetherelationshipbetweenSSRItreatmentandmaniainmoresystematicways.Somestudies'findingssuggestthatantidepressantsmightincreasetherateofmania.Faedda,Baldessarini,GlovinskyandAustinreportedarateof48.7%ofchildrenwithbipolardisorderdevelopingmaniafollowingtreatmentwithaSSRI(n=19of39exposed)[70].Theantidepressantinducedmanicepisodewastheepisodethatinitiatedthebipolardiagnosisinonly17%ofthosecases.Themedianlatencytomaniawas12.5days(acrossallclassesofantidepressantsandstimulants).AnotherchartreviewofyouthswithbipolardisorderrevealedthatthosereceivingSSRItreatmentwerethreetimesmorelikelytoreportmanicsymptomsattheirnextfollowupvisitthanyouthswhodidnottakeaSSRI[71].Wilensandcolleagues,whenreviewing82consecutiveadmissionstoapediatricpsychopharmacologyunitwhowereprescribedanSSRI,foundthatfiveoftheyouth(6%)haddevelopedmanicsymptomswhiletakingtheSSRI[72].Areviewof79consecutivehospitaladmissionsshowedthatyouthswhohadeverreceivedanantidepressanthadanearlierageofonsetofbipolardisorderthanyouthswhohadnot[73].However,thelatterstudydidnotlookattheeffectoftreatmentwithaSSRIseparatelyfromotherclassesofantidepressants.ThepatternoffindingsinthesestudiescouldbeexplainedbytheIgnitionorScarhypotheses,butitalsoisconsistentwiththeBipolardepressionhypothesis:youthswithbipolardisordermightoftenhaveearlieragesofonsetfortheirdepression,leadingtoearlierantidepressantprescription.Anotherchartreviewstudyexamined'druginducedbehavioraldisinhibition',andfoundthatratesincreasedsignificantlywithSSRIusage[74].Astrengthofthisstudywasthatitincludedobjectivebehavioralindicators,suchasnumberofseclusionsbutitisnotclearhowmuchoverlapthereisbetween'behavioraldisinhibition'andmania.

Apharmacoepidemiologicstudyofageeffects[18]examinedconversiontomaniainchildren,adolescents,andyoungadultswithanxietyornonbipolarmooddisorders.Theauthorsanalyzedmentalhealthoutpatientandpharmacyclaimsof87,920individuals,aged529years,overamedianof41weeks.Thestudyshowedanoverallprevalenceofmanicconversionof5.4%.Atotalof49%oftheconvertershadbeenexposedtoaSSRI.SSRItreatmentwasassociatedwithahazardratioof2.1,roughlyatwofoldincreaseintheriskofconversiontomania.Thiseffectsizeisconcerning,yetalso

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smallenoughthatEvidenceBasedMedicineauthoritiespointoutthatitcouldbeentirelyattributabletoextraneousfactorsbesidesaniatrogeniceffect[28].TheauthorsreportedthatamongthosetreatedwithSSRIs,youthyoungerthan15yearsofagewereatanincreasedriskformania.Again,thisdesigncannotdistinguishbetweentheBipolardepressionhypothesisversusthethreeiatrogenicpossibilities.

Inoneofafewstudiesspecificallyexaminingantidepressantinducedmaniainyouthswithbipolardisorder,Baumeretal.foundthatamong52childrenandadolescentswithoratriskforbipolardisorder(operationalizedbyhavingaparentwithbipolardisorder),50%experiencedeitheranewmanicepisodeoraworseningofanexistingepisodeafterbeingtreatedwithvariedantidepressants,approximately80%ofwhichwereSSRIs,foranaverageof1.4years[11].Inachartreviewstudythatfollowedyouthsfor12monthsafterfirsthospitaladmissionforeitheramanicoramixedepisode,antidepressantusewasassociatedwitharecurrenceofamoodepisode[75].Thereportingofthisstudydidnotdifferentiatebetweenmanicversusdepressedrecurrence,though,andotheraspectsofthefindingsindicatethattreatmentrefractorinessofdepressionmightbeinfluencingresults.

Otherstudieshavefoundnoeffectofantidepressantsontheageofonsetofbipolarorthemanicsymptomsobservedinyouthswithbipolardisorder,includingretrospectiveinterviewreportaboutageofonsetandcurrentinterviewbasedmoodratingsinanoutpatientsetting[76].Similarly,Soutulloandcolleaguesfoundthatamonghospitalizedadolescentswithbipolardisorder,ahistoryofexposuretoantidepressanttreatmentwasnotassociatedwithamoreseverecourseofhospitalizationasmeasuredbylengthofstayinthehospital,numberof'asneeded'medicationsgiven,orseclusionandrestraintorders[77].Attheotherextreme,astudyofyouthswithpsychoticdepressionfoundthatantidepressantusewasassociatedwithafourfolddecreaseinriskofdevelopingmaniaoverthefollowupperiod,withcasesfollowedforaslongas2years[78].

Alongitudinalstudylookingatthedevelopmentofmaniainacohortofyouthsoriginallyidentifiedashavingattentiondeficit/hyperactivitydisorderbutnocomorbidmooddisorderisalsorelevant[79].Theyouthswereoriginallyascertainedasacomparisongroupforalongitudinalstudyofpediatricbipolardisorder,with6yearfollowupdataprovidingthebasisforanalysis.Basedonblindedinterviews,29%developedbipolarIwithelationorgrandiosity.Antidepressantusewasnotsignificantlyassociatedwithdevelopingmania.ThesefindingscouldbeconsistentwiththeBipolardepressionhypothesis:systematicallyexcludingcaseswithpediatricdepressionmayhaveeliminatedcasesinitiallyidentifiedasdepressedwhowouldlaterhavecycledintomania.Excludingthesemighthaveeliminatedtheartifactthatisinterpretedasshowinga'switch'tomaniainotherstudies.

Inshort,thechartreviewstudies(includingthosewithfollowup)havefoundinconsistentresults,andthedesignshavenotbeenstrongforexaminingtheissueofantidepressantusageprecipitatingmania.Thestudieswithafollowupcomponent,highretentionandthemoststructuredassessmentsofmaniahavetendedtoproducethesmallesteffects.Overall,thesefindingsappearmostconsistentwiththeVigilanceandBipolardepressionhypotheses.TheMedicationasirrelevanthypothesisappearsatleastasplausibleasanyoftheIatrogenichypothesesbasedonthedata.

Clinicaltrials

SeveralresearchgroupshavereportedmaniaasanadverseeventduringbothopenlabelandRCTsexaminingSSRIsastreatmentforchildrenandadolescents.

Citalopram

Among174youthstreatedfordepressionwithcitalopramorplaceboinaRCT,nonedevelopedmania,althoughadverseeventswerereportedspontaneouslyandmaniawasnotformallyassessed[80].Inanopenlabeltrialofcitalopramtreatmentforearlyonsetmajordepressivedisorder(MDD),ShiraziandAlaghbandRadfoundthatoverthe6weekstudyperiod,16.7%ofchildrenandadolescentsexperiencedanunexpectedswitchtomania[81].Sincethedesignwasanopentrial,itisparticularlyvulnerabletotheVigilanceissueandbecausethereisnocomparisongroup,thefindingsdonotprovideinformationregardingincreaseofrisk[28].

Escitalopram

Of264childrenandadolescentstreatedwithescitalopramorplacebofordepression,onedevelopedmaniahowever,thisoccurredintheplacebocondition[82].Adverseeventreportingwasspontaneousorobservational.

Fluoxetine

PerhapsthebestknownstudyoffluoxetineforadolescentdepressionistheTreatmentofAdolescentDepression(TADS)trial[30].TheTADStrialspecificallyassessedforthedevelopmentofmanicsymptoms.Fluoxetinewasgiveneitheraloneorincombinationwithcognitivebehavioraltherapy.Foursubjects(3.67%)onfluoxetinealoneandone(0.93%)inthecombinationarmdevelopedsymptomsonthemaniaspectrumduringtreatment,versusoneonplaceboandnonein

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thecognitivebehavioraltherapyonlyarm.However,threeofthefivewhodevelopedmaniabeganthetrialwithhighbaselinemaniasymptomscoresasassessedbytheAdolescentDepressionScale,developedspecificallyfortheTADStrial.Atotalof38patientsoverallbeganfluoxetinetreatmentwithhighbaselinemaniascorestherefore,most(92%)ofpatientsactuallytoleratedfluoxetinewellwithrespecttothedevelopmentofmaniaorhypomania.

Inanotherdoubleblind,randomized,placebocontrolledtrialoffluoxetinefordepressedchildrenandadolescents,6.25%(n=3)ofyouthsreceivingfluoxetineexperiencedamanicepisodeduringtreatmentversusarateof2%(n=1)onplacebo[83].Inasecondrandomized,placebocontrolledtrialoffluoxetineforyouthswithdepression,oneparticipantoutof109developedamanicreactionwhilenoparticipantsintheplacebogroup(n=110)did.Thisdifferencewasnotstatisticallysignificant[3].Intherelapsepreventionphaseofthistrial,therewerenoreportsofmaniaamong20patientsremainingonfluoxetine,althoughwhetheritwasspecificallyassessedforwasnotstated[84].Go,MalleyandBirmaherreportedthatduringopenlabelclinicaltreatment,30%of40youthswithobsessivecompulsivedisorder(OCD)andmooddisordersdevelopedmanicorhypomanicsymptomswhentreatedwithfluoxetineorsertraline[59].Becausethestudywasopenlabel,theVigilancehypothesisisamajorconcern.Owingtothecomorbidmooddisorders,theBipolardepressionhypothesisisalsoviable.

Fluvoxamine

An8weekRCToffluvoxaminetreatmentforanxietydisorders,aswellasa6monthopenlabelfollowuptrialof128participantsfromthe8weektrial,failedtoidentifyanyyouthsexperiencingmania[85,86].Neitherpublicationspecificallystatesthattherewasnooccurrenceofmania,norisitclearwhatassessmentstrategy,ifany,wasusedtoassessforhypomaniaormania.

Paroxetine

InaRCTofparoxetinetreatmentfor206childrenandadolescentswithMDD,adverseeventswere'gatheredbyspontaneousreport',andnoincidentsofmaniawerereported[7].Thedevelopmentofmaniawasnotspecificallyassessed.

Sertraline

McConvilleandcolleaguesfoundthatoneoutofeighthospitalizedadolescentswithMDDdevelopedmaniaduringopenlabelsertralinetreatment[87].WagnerandcolleaguesconductedtwolargetrialsofsertralinetreatmentforMDDinchildrenandadolescentshowever,thesetrialsfailedtospecificallyassessformania,andnonewasreported[4].WhensertralinewasusedtotreatOCDin137childrenandadolescents,bothduringa12weekrandomizedplacebocontrolledtrial[88]andduringa52weekopenlabelextensionstudy[89],noneoftheparticipantsexperiencedmanicorhypomanicsymptoms.ThesefindingsareconsistentwiththeBipolardepressionhypothesisthe'switch'tomaniaappearswhenpeoplehavedepression,butnotwhentheyaretreatedwithantidepressantsforotherconditions(e.g.,attentiondeficithyperactivitydisorder)[79].Thepatternsuggeststhatitisthedepression,nottheantidepressant,thatappearsmorelinkedtothemania,aswasalsothecaseintheTADStrial(seeabove).

Venlafaxine

IntheTreatmentofSSRIResistantDepressioninAdolescents(TORDIA)trial,oneparticipantoutof83randomizedtoreceivevenlafaxinedevelopedhypomania[31],assessedusingamaniascreenandtheManiaRatingScale.Inthesametrial,noparticipantsdevelopedmaniaamong168randomizedtoreceivefluoxetine,paroxetineorcitalopramand83randomizedtoreceivevenlafaxineincombinationwithcognitivebehavioraltherapy.

Theratesreportedhereformaniaasanadverseeventduringclinicaltrialsmayactuallyunderestimatethetruerisk,asparticipantswithafamilyhistoryofbipolardisorderwereexcludedfrommostofthesestudies.Hadthesetrialsincludedyouthswithahigherriskofexperiencingmaniaevenintheabsenceofexposuretoantidepressanttreatment,ratesofmaniaduringSSRItreatmentmighthavebeenhigher.Ironically,therealsoappearstobeaconfound,wherethestudieswithstrongerdesigns(randomized,blindedandplacebocontrolledtrials)mayhavehadlessthoroughorsystematicassessmentofmanicsymptoms,whereasopentrialsmayhavebeenmorevigilanttothepossibilityofmanicsymptoms.ItisagainunclearwhetherSSRItreatmentcausedthemanic/hypomanicsymptoms,orwhetherthesemayhaveemergednaturallyinthecourseofanexistingmooddisorder,buttheweightoftheevidenceappearstofavortheBipolardepressionhpothesismorethananyoftheIatrogenichypotheses(ignition,scarorsideeffect).

Riskversusbenefitanalysis

TheEvidenceBasedMedicineframework[28]alsoprovideswaysofquantifyingthestrengthofassociationbetweenantidepressantsandmania.Theseincludetherelativerisk(RRtheratiooftheratesofmaniaintheantidepressantexposedgroup,dividedbytherateinthenonantidepressantcomparisongroup),theoddsratio(oddsofmaniainthe

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antidepressantgroupdividedbyoddsofmaniainthecomparisongroup)andthenumberneededtoharm(NNH).TheNNHisthereciprocalofthedifferenceintheratesofmaniaintheantidepressantexposedversuscomparisongroup.Conceptually,theNNHisthenumberofpatientsthatwouldneedtobeexposedtoantidepressantsbeforeonemoreonaveragewoulddevelopmania.TheNNHhasacorrespondingmeasureofthemagnitudeofbeneficialtreatmenteffects,thenumberneededtotreat(NNT)inorderforonemorepatienttohaveagoodoutcome.TheNNTandNNHcanbecombinedtocreatealikelihoodofhelpversusharm(LHHthereciprocalsoftheNNTdividedbythereciprocaloftheNNH,sothatlargernumbersindicategreaterprobabilityofbenefit).

Whatwouldthesemetricssuggestabouttherelationshipbetweenantidepressantsandmania?Wefocusonfluoxetineasanexample,because:first,fluoxetinehasthebestevidenceofefficacyforpediatricdepression[6]second,fluoxetineappearstobeassociatedwithsomewhathigherratesofmaniathanotherSSRIs[90]andthird,fluoxetinehasmultiplepublishedRCTswheretheratesofmaniacanbecomparedwithratesinarandomlyassignedplaceboarm,providingsomeofthebestevidenceavailableontheissue[3,59,83].PoolingtheresultsofthethreeRCTs,therateofmaniaonfluoxetinewas2.8%,versusarateof1.0%onplacebo.TheRRofmaniais2.8,approachingtherangewhereweshouldbeconcerned(RR3wouldbe'convincing')[28].TheNNHis56,meaningthatforevery56youthsexposedtofluoxetine,onaverageonemorewoulddevelopmania.TheNNHestimatedseparatelyforeachRCTrangedfrom24to145.Ontheotherhand,fluoxetineappearedefficaciousacrossallthreestudies,withNNTestimatesrangingfrom3.8to6.5,andapooledestimateof4.7.TheLHHis11.8whenallthreestudiesarecombined,andrangedfrom6to22forthestudiesseparately.Thus,whenfocusingonthecompoundwiththemostevidenceforefficacyandalsothegreatestconcernaboutmaniaasanadverseevent,patientsappearroughly12timesmorelikelytobenefitthantoexperiencemaniaandeventheworstcasescenarioisthatpatientswouldstillbesixtimesmorelikelytobenefit.EstimatingtheLHHseparatelyforseveralstudiesisonewayofconductinga'sensitivityanalysis',orexaminingtheextenttowhichtheLHHestimatechangesdependingonthestartingvalues.Sensitivityanalysescanalsoinclude'whatif'scenarios,wheretheLHHisrecalculatedusingmoreliberalorconservativeestimatesofrisk,sothatthedecisionmakerscanunderstandtheeffectsofchangingassumptionsonthefinalestimates[28].

ItispossibletofurthercustomizetheLHH,addingadditionalinformationaboutindividualfactorsaffectingtheprobabilityofriskorbenefit,aswellasincorporatingpatientpreferences.Strausetal.providedetailedexamplesofaddingthesefactorsintotheequation(seepage139143[28]).Onaverage,includingpatientpreferenceswilltypicallyshiftthebalanceevenfurtherinfavorofbenefitinsteadofharm.Twomajorreasonsforthisaretheevidencethatdepressioncreatesmoreburdenthanmania,andhasaworseeffectonqualityoflife[91]andalsobecausedepressionisthemorelethalphaseoftheillness(includingbeingamajorcomponentofmixedstates)[44].Italsomaybepossibletoshiftthebalancefurtherbyprovidingpsychoeducationtothefamily,usingcarefulmonitoringtodetectmania,andestablishingaplanformanagingmanicsymptomsshouldtheyemerge.Byincreasingtheknowledgeandtheexternalsupportsavailable,therisksassociatedwithmaniamaybemorecontained.Withclosemonitoring,itismorelikelythattreatmentcouldbechangedduringhypomaniaratherthanwaitinguntilfullblownmaniamanifests.Atthesametime,theirritablemoodandaggressionfrequentlyassociatedwithpediatricmaniaareoftenachiefconcernoffamiliesandamajortreatmenttarget[92],sointerventionsthatincreasetheriskofdisinhibited,aggressivebehaviormayrequiremorecaution.

Limitations

Thereareseveralimportantlimitationstokeepinmind,bothaboutthestateoftheliterature,andalsoaboutthisparticularreview.Decisivestudiesabouttherelationshipbetweenantidepressantsandmaniahavenotbeenconducted,soitisimpossibleforareviewtodrawdecisiveconclusions.Somelimitationsoftheliteratureinclude:

*Mostpublishedarticlesdonotsatisfymostofthecriteriaforprovidingavalidsourceofinformationaboutriskofharm[28].Casereportsarenotadequate,unlessperhapstheyusedrechallenge,ABABdesigns,buttheseareclinicallynotconducted.SeeBox1foralistoftheguidelinesandothercommentsonthestateoftheliterature

*Therearelargedifferencesintheratesofmaniaidentifiedacrossstudiesandinconsistenciesinthesizeofthefindings,makingitplausiblethatmethodologicalissues(suchastheVigilanceorFalseAlarmhypotheses)orthenaturalcourseofbipolardisorder(consistentwiththeMedicationasIrrelevantortheBipolarDepressionHypotheses)explainthefindings,insteadofoneoftheproposediatrogenicmechanisms

*Therearemajordifferencesintheoperationaldefinitionofmaniaacrossstudies,andequallylargedifferencesinhowmaniaisassessedThesemakeitmuchmoredifficulttointerpretfindings

*Theremaybelocalandhistoricalchangesinpatternsofdiagnosis.Thesteepincreasesintherateofbipolardiagnosesshowsthattherehavebeendramaticchangesinpracticethatareindependentofchangesinactualrateofincidence.Cliniciansmaybecomehypervigilanttothepossibilityofmania.Cognitiveheuristicsandpublicationbiasbothwillleadtooveremphasizingthedegreeofrisk

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*Manychartreviewsandclinicaltrialsexcludedbipolaryouth.Wedonotknowratesofswitchingfortheseyouth(versusyouthwithanxietyorMDDthathasnotyetshownitselftobebipolar)[cf.76],althoughtheadultliteraturesuggestsitcouldbehigherthanwhatweareseeinghere.Conversely,studieswithyouthsexposedtoantidepressantswhodidnothaveahistoryofdepressionhaveconsistentlyfoundlowratesofmania[9395].Thetwocompetingexplanationsforthispatternoffindingsarethatassessmentofmaniainthesestudiesisnotsufficientlysystematictobesensitivetoinstancesthatactuallyareoccurring(avariantoftheVigilancehypothesis),orthatitispreviouslyundiagnosedbipolardisorderthatwasbeingtreatedfordepression,andthensubsequentlymanifesteditsassociatedmanicsymptoms(theBipolardepressionhypothesis).Theinsufficientsensitivityargumentislessofaconcerngiventhatoneofthestudiesfindingnoincreaseinriskwasasecondaryanalysisoflongitudinaldatafromoneoftheleadinginvestigationsofpediatricbipolardisorder[79].

Anadditionallimitationofthisreviewisthatitdoesnotattempttometaanalyzetheexistingstudies,relyinginsteadonqualitativewaysofappraisinganddescribingthefindings.Theliteraturedoesnotyetseemlargeenoughtosupportameaningfulmetaanalysis,particularlywithsofewstudiesreportingadequateinformationtoestimaterelativerisks.

Conclusions

Therehasbeenwidespreadconcernthatantidepressantsmightbeassociatedwithmania,bothatthelevelofindividualcasesandnowatthepublichealthlevel.MedicationexposureisoneofthepotentialfactorsunderdiscussionfortherisingratesofpediatricmaniaintheUSA[24].Practitionerswantclearguidanceabouttheriskssothattheycanavoidthepotentialharmoftriggeringmaniasinpatientswithdepression.Itisalsounclearwhetherantidepressantsshouldbeinthearmamentariumoftreatmentoptionsformanagingpediatricmooddisturbanceand,ifso,forwhichpatients.Theavailableliteratureiscomplexandinconsistent,makingitdifficulttoformaneducatedopinionquickly.

Thisreviewattemptstomovebeyonda'boxscore'approachoftallyingthenumberofstudiesfindingevidenceforantidepressantsinducingmaniaornot.Westartedbylayingoutsevendifferentmodelsofhowantidepressantscouldappeartobeassociatedwithmania.Threewerevariationsofiatrogenicmodels,whereantidepressantsmightigniteapreexistingdiathesisformania,createanewandlingeringriskformaniaorcreatemanicsymptomsasatemporarysideeffectofthecompound.Twoofthemodelspertaintothenaturalcourseoftheillness:onearguesthatmaniaoccursindependentofthemedication,thatantidepressantsareirrelevant(orperhapsevenslightlyprotective).ThesecondbuildsontheNaturalcourseHypothesisbypointingoutthatcliniciansaremostlikelytoencounterbipolarillnessduringthedepressedphase,thatthefirstphaserequiringtreatmentisalsooftendepressionandthatearlierageofonsetfordepressionappearstobeassociatedwithbipolardisorder.Inshort,aconstellationoffactorsmayberesultinginasubstantialportionofpediatricdepressionactuallybeingonthebipolarspectrum.Ironically,aconservativestanceaboutpediatricbipolardisordercouldresultinanunderestimationoftheriskfactorsandwarningsigns,leadingtoaninitialunderdiagnosisofbipolardisorderthatthenappearsto'switch'tomaniaasthepractitionerfollowsthepatient.Thefinaltwomodelsaremethodologicalartifactsthatareoftencalled'confounds'.Skepticsoftenraisethepossibilitythatpediatricbehavior'withinthenormallimits'ismistakenlypathologized.TheVigilancemodelholdsthatapparentchangesinratesofmaniaaredrivenbyshiftsinthesensitivityofclinicaldiagnoses.

Whatbecomesclearoverthecourseofthereviewisthattheiatrogenicmodelsarethemostprovocativeandthemethodologicalartifactsaretheleastlikelytocommandattention.However,theweightoftheevidenceappearstosuggestthatsomeoftheleaststirringordiscussedmodelsmayactuallyhavethemostsupport.Conversely,theiatrogenicmodelshavenotaccumulatedstrongevidencedespitethehighlevelofconcerntheyinviteandtheevidenceisweakestintheRCTsthathavethestrongestdesigns.

Onthebasisofthisreview,theconclusionistoproceedwithcaution.BasedontheLHHframeworkfromEvidenceBasedMedicine,antidepressantsappeartoofferaclearnetbenefitfortheaveragepatient.TheEvidenceBasedMedicineapproachalsoofferspractitionersawayofcustomizingandpersonalizingclinicaldecisions,takingintoaccountindividualriskfactorsandpreferences.Thescaleswilltipfurtherinfavorofantidepressantusageincaseswherethedepressionissevereorrefractory,andwheretherisksofmaniacanbecontainedbyprovidinggoodpsychoeducationtothefamilyanddeployingcarefulassessmenttoolsthatwillbesensitivetotheemergenceofmaniaorsideeffects.Incaseswherethereisafamilyhistoryofbipolardisorder,orcaseswithahistoryofimpulsiveaggressivebehavior,thenthebalancewouldshiftawayfromSSRIusage(althoughtheevidenceofharmisnotmuchmorewellfoundedforthesecasesthanformaniaingeneral).

Futureperspective

Therearemanywaysthatthesituationwillimproveoverthenext5to10years.Theclinicalconcernthatantidepressantsmightinducemaniahasraisedawarenesstothepointthatfuturestudiesusingantidepressantsmaydothesystematicassessmentofmanicsymptomsbothlifetimehistorypriortoenrollment,aswellaslookingforemergenceduringtreatmentneededtodecisivelyaddresstheissue.Improvedassessedtoolsarealreadyavailable(see[96]forreviewanddiscussionaboutimplementation),andiftheyareadoptedmoreinresearchandclinicalpracticetherewillbeimmediateimprovementsinthemanagementofpediatricmooddisorder.Inthenearfuture,therewillbecontributionsfromthe

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personalizedmedicinevantagetoo,withimprovedassessmentintermsofgenotyping(includingidentificationofindividualdifferencesinresponsetomedication)[97],metabolicmeasuresofphysiologicalresponsetomedication,andtheuseofnoninvasivetechnologies(suchasactimetryorcellphonebasedlifecharting)toprovidemorerapidandobjectivemeasuresofmoodchange.Althoughtheissueofantidepressantsandmaniahasbeencomplexandcontentiousinthepast,researchisbeginningtomakecontributionstoevidencebasedtreatment,andthepacewillacceleraterapidly.

Box1.Criteriaforevaluatingwhetherevidenceaboutantidepressantinducedmaniaisvalid.Criterion Evaluationoftheliterature

1.Werethereclearlydefinedpatientgroupsthatweresimilarinallwaysotherthanexposuretoanantidepressant?

Nocomparisongroupincasestudies.Comparisongroupsdifferacrossotherstudies.

2.Weretreatmentsandmanicsymptomsmeasuredthesamewayinbothgroups?Wastheassessmentofmaniaobjectiveorblindedtoantidepressantexposurestatus?

Openlabeltrialsandcasestudiesnotblinded.

3a.Wasthefollowupperiodsufficientlylongformaniatooccur? Variable,butoftensufficient(extendingouttoayearormore).

3b.Wasretentionadequate?Howweremissingdatatreated?

Strausetal.[28]offeraruleofthumbofignoringanystudywithmorethan20%losttofollowup,becausethiswilllikelyintroducebias.Missingdataareoftennotdiscussedinpublishedreportsonantidepressantsandmania.

4.Dotheresultssatisfysomeofthediagnostictestsforantidepressantscausingmania?4a.Isitclearthatantidepressantexposureprecededtheonsetoftheoutcome?

Ifassessmentofmaniaisnotrigorousatbaseline,thenpriorhypomaniacanescapedetection.

4b.Isthereadoseresponsegradient? Doseresponsehasnotbeendemonstratedforantidepressantinductionofmaniayet.4c.Isthereanypositiveevidencefromawithdrawalrechallengestudy?

Wehavenotfoundarechallengestudyintheliterature.Thereisablindedwithdrawalstudy[98].

4d.Istheassociationbetweenantidepressantsandmaniaconsistentfromstudytostudy?

No.Resultsrunthefullgamutfromincreasedratesofmania,tonodifferenceinrates,tosignificantdecreasesinratesofmania.

4e.Doestheassociationbetweenantidepressantsandmaniamakebiologicalsense? Yes,clearly.

Adaptedfrom[28].

Executivesummary

Background

*Thedecisivestudytoestablishtheriskofanantidepressanthasnotbeenconducted.Thiswouldrequireadoubleblinded,placebocontrolledtrialwithexcellentassessmentofmanicsymptoms,includingalifetimehistorypriortorandomization,andalongenoughfollowuptocapturethemajorityofsubsequentmanicevents.

*Antidepressantinducedmaniainadultsisagenerallyacceptedclinicalphenomenon,evenintheabsenceofsuchadecisivestudy.

*Theexistingliteratureregardingpediatricantidepressantusageandmaniaisalmostentirelybasedondesignspronetobias.

Modelsoftherelationshipbetweenantidepressants&mania(&sevenpotentialpitfalls&remediesforpractitioners)

*Ignitionhypothesisuncoveringalatentdiathesis,turningongenesthatwerealreadypresent.Althoughofgreatconcern,thereislittlesupportingevidenceforthisfromstudieswithstrongerresearchdesigns.

*Scarhypothesiscreatinganewdiathesisintheabsenceofpriorbiologicalrisk.Thisisperhapsthemostworrisomehypothesis,andalsooneofthemostspeculative,withnodirectsupportingevidenceyetintheliterature.

*Sideeffecthypothesistemporarydeleteriouseffectofdrug,butnotatruemanifestationofabipolarillness.Thishypothesisappearstobeplausible,buttheeffectsappeartoberareinstudieswithstrongdesigns.

*Vigilancehypothesisincreasedmonitoringfortheillness,butnoactualchangeinrisk.Thishypothesisislikelyto

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contributetothehighratesofmaniaobservedinopentrials,whichironicallyoftenhaveusedbettermonitoringofmanicsymptomsthanmanyoftheblinded,randomized,controlledtrials.

*Medicationasirrelevanthypothesiswhatwearewitnessingisthenaturalcourseofthebipolarillness,notaresponsetothetreatment.Thishypothesisappearsconsistentwithlongitudinaldataaboutcourseofillnessandepidemiologicaldataitcanalsoaccountformuchoftheapparentlyhighrateofmanicsymptomsemergingduringthecourseoftreatmentformooddisorders.

*Falsealarmshypothesismislabelingjuvenilebehavioraspathologicalwhenitstillfallswithinnormallimitsmistakingirritabilityduetoothercausesasanindicatorofpediatricmaniaoralternately,mistakingthereturnofenergyandpositiveemotionsasdepressionliftsforhypomania.Thisisalsoaplausiblehypothesis,especiallygivenemergingevidenceoflargedifferencesindiagnosticformulationsforsimilarsymptompresentationsacrosspractitioners,clinicsandevencountries.

*Bipolardepressionhypothesiswhentreatingyouthsfordepression,weareoftendealingwiththedepressedphaseofwhatwillprovetobeabipolarillness.Thisappearstobealikelycontributortotheratesofmanianotedduringtreatmentofmood,andactuallycouldexplainseeminglyhigherratesinyouthsthanadultsbecauseofthepossibilitythatbipolardepressionwillbethefirstphaseofillnesstodrivetreatmentseeking.

Reviewoftheevidenceforantidepressantspotentiallyinducingmania

*Casestudiesofselectiveserotoninreuptakeinhibitor(SSRI)inducedmaniainyouthsarecommon,butaddlittleevidenceabouthowpatientsshouldbetreated.Casestudiesarebiased'youthonantidepressantsfailstobecomemanic'isunlikelytobepublished.

*PublishedchartreviewstudiesofSSRIcoincidentmaniagenerallyfailtomeetguidelinesfordemonstratingclearevidenceofharm.

*Clinicaltrialsexistformostoftheantidepressantsusedwithyouthshowever,theassessmentandreportingofmanicsymptomswasnotrigorousinolderstudies.Thiscouldleadtounderestimatingabsoluteratesofmania,butshouldnotbiasestimatesofrelativeriskforantidepressantsversusplacebo.

Riskversusbenefitanalysis

*Depressionisworsethanmaniaintermsofburdenontheindividualandriskofsuicide.Thegreaterriskandburdenmaytipthescaleinfavorofcontinuingtouseantidepressantstomanagethedepression,withclosemonitoringformania.

*Fluoxetinehasthebestcurrentdataabouttreatmentefficacy,andalsosomeofthegreatestconcernsaboutpotentialassociatedmania.Basedonthreerandomizedtrials,thelikelihoodofhelpversusharm(mania)onfluoxetineismorethan11,favoringantidepressantuse,beforeconsideringpatientcharacteristicsorpreferences.

Limitations

*Decisivestudieshavenotbeencarriedout.Theliteraturedoesnotsupportaclear'finalanswer'abouttherelationshipbetweenantidepressantsandmania.

Conclusions

*Proceedwithcaution.Despitethegreatconcernaboutthepossibilityofantidepressantsincreasingtheriskofmania,thestudieswiththestrongestresearchdesignsfindthesmallestevidenceofrisk.

*Patientsonfluoxetinearemorethantentimesmorelikelytobenefitthanexperiencemania.Takingpatientpreferencesintoaccountwilloftentipscalesfurthertowardsantidepressantusagetomanagemood.

*Educationaboutmedicationandsideeffectsandcarefulmonitoringformaniawillfurthercontainrisks.

Futureperspective

*Personalizedapproachestomedicine,includinggeneticandmetabolictestingaswellastechnologicalimprovementsinassessmentofmoodandenergy,willsoonprovidepowerfultoolstohelpgaugeriskandresponsetoantidepressantsaswellasothertreatmentregimens.

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AuthorAffiliation(s):

1UniversityofNorthCarolinaChapelHill,DepartmentofPsychology,CB#3270,DavieHall,ChapelHill,NC27599,USA.megan.joseph@unc.edu

2UniversityofNorthCarolinaChapelHill,DepartmentofPsychology,CB#3270,DavieHall,ChapelHill,NC27599,USA.eay@unc.edu

3UniversityofNorthCarolinaChapelHillSchoolofMedicine,DepartmentofPsychiatry,CB#7160,10612NeurosciencesHospital,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,havenofinancialrelationshipswithanypharmaceuticalcompany.JairSoares,MD,isonthespeaker'sbureauatEliLillyandAstraZeneca,isaconsultantforOrganonandShire,andreceivesgrantfundingfromPfizerandGlaxoSmithKline.Theauthorshavenootherrelevantaffiliationsorfinancialinvolvementwithanyorganizationorentitywithafinancialinterestinorfinancialconflictwiththesubjectmatterormaterialsdiscussedinthemanuscriptapartfromthosedisclosed.

Nowritingassistancewasutilizedintheproductionofthismanuscript.

MeganFJoseph,EricAYoungstrom,JairCSoares

SourceCitation(MLA7thEdition)

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Joseph,MeganF,JairCSoares,andEricAYoungstrom."Antidepressantcoincidentmaniainchildrenandadolescentstreatedwithselectiveserotoninreuptakeinhibitors."FutureNeurology4.1(2009):87+.AcademicOneFile.Web.26Apr.2015.

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