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Mixedstatesinbipolarandmajordepressive Mixedstatesinbipolarandmajordepressive

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Mixedstatesinbipolarandmajordepressive - PPT Presentation

Review disorderssystematicreviewandquality appraisalofguidelines VerdoliniNHidalgoMazzeiDMurruAPacchiarottiISamalinL YoungAHVietaECarvalhoAFMixedstatesinbipolarandmajor depressivedisorderss ID: 942422

blind placebo isbd double placebo blind double isbd cinp canmat olz olanzapine wfsbp controlledstudy arandomized asn guidelines arp vpa

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Review Mixedstatesinbipolarandmajordepressive disorders:systematicreviewandquality appraisalofguidelines VerdoliniN,Hidalgo-MazzeiD,MurruA,PacchiarottiI,SamalinL, YoungAH,VietaE,CarvalhoAF.Mixedstatesinbipolarandmajor depressivedisorders:systematicreviewandqualityappraisalof guidelines. Objective: Thissystematicreviewprovidedacriticalsynthesisanda comprehensiveoverviewofguidelinesonthetreatmentofmixedstates. Method: TheMEDLINE/PubMedandEMBASEdatabaseswere systematicallysearchedfrominceptiontoMarch21st,2018. Internationalguidelinescoveringthetreatmentofmixedepisodes, manic/hypomanic,ordepressiveepisodeswithmixedfeatureswere consideredforinclusion.Amethodologicalqualityassessmentwas conductedwiththeAppraisalofGuidelinesforResearchand Evaluation-AGREEII. Results: TheÞnalselectionyieldedsixarticles.Despitetheir heterogeneity,allguidelinesagreedininterruptinganantidepressant monotherapyoraddingmood-stabilizingmedications.Olanzapine seemedtohavethebestevidenceforacutemixedhypo/manic/ paliperidonewerepossiblealternativesforacutehypo/manicmixed states.Lurasidoneandziprasidonewereusefulinacutemixed depression.Valproatewasrecommendedforthepreventionofnew mixedepisodeswhilelithiumandquetiapineinpreventingaective episodesofallpolarities.Clozapineandelectroconvulsivetherapywere eectiveinrefractorymixedepisodes.TheAGREEIIoverall assessmentraterangedbetween42%and92%,indicatingdierent qualitylevelofincludedguidelines. Conclusion: Theunmetneedsforthemixedsymptomstreatmentwere associatedwithdiagnosticissuesandlimitationsofpreviousresearch, particularlyformaintenancetreatment. N.Verdolini 1,2,3,4 ,D.Hidalgo- Mazzei 1,3,5 ,A.Murru 1,3 , I.Pacchiarotti 1,3 ,L.Samalin 1,6,7 , A.H.Young 5 ,E.Vieta 1,3 , A.F.Carvalho 8,9 1 BipolarDisorderUnit,InstituteofNeuroscience, HospitalClinic,IDIBAPS,CIBERSAM,Universityof Barcelona, 2 FIDMAGGermanesHospital  ariesResearch Foundation,SantBoideLlobregat, 3 CIBERSAM,Centro Investigaci  onBiom  edicaenRedSaludMental, Barcelona,Spain, 4 DivisionofPsychiatry,Clinical PsychologyandRehabilitation,DepartmentofMedicine, SantaMariadellaMisericordiaHospital,Universityof Perugia,Perugia,Italy, 5 DepartmentofPsychological Medicine,CentreforAffectiveDisorders,Instituteof Psychiatry,Psychology&Neuroscience,King ’ sCollege London,London,UK, 6 DepartmentofPsychiatry,CHU Clermont-Ferrand,UniversityofAuvergne,Clermont- Ferrand, 7 FondationFondaMental,P ^ oledePsychiatrie, H opitalAlbertChenevier,Cr  eteil,France, 8 Departmentof Psychiatry,UniversityofToronto,and 9 Centreof AddictionandMentalHealth(CAMH),Toronto,ON, Canada Keywords:mixedstates;mixedfeatures;bipolar disorder;unipolardisorder;guidelines EduardVieta,BipolarDisorderUnit,Instituteof Neuroscience,HospitalClinic,IDIBAPS,CIBERSAM, UniversityofBarcelona,170Villarroelst,12-0,08036 Barcelona,Spain. E-mails:EVIETA@clinic.cat;NVERDOLINI@clinic.cat AcceptedforpublicationApril17,2018 Summations  Olanzapineseemedtobethemosteectivecompoundforthetreatmentofacutemixedhypo/manic ordepressivestatesaswellasforthepreventionofaectiveepisodesofanypolarity,eventhoughthe availableevidencewasstillscant.  Aripiprazoleandpaliperidoneinmonotherapycouldbeeectivealternativesinthetreatmentof acutehypo/manicmixedstateswhilelurasidoneandziprasidone(incombinationwithtreatmentas usual)inthetreatmentofacutedepressivemanifestations.Asforthemaintenancetreatment,val- proatewaseectiveinthepreventionofnewmixedepisodes.Lithiumandthecombinationtreatment ofquetiapinewereusefulinpreventingaectiveepisodesofallpolarities.  Antidepressantmonotherapyshouldbeavoidedwhileclozapineandelectroconvulsivetherapywere 1 ActaPsychiatrScand2018:1–27 © 2018JohnWiley&SonsA/S.PublishedbyJohnWiley&SonsLtd Allrightsreserved DOI:10.1111/acps.12896 ACTAPSYCHIATRICASCANDINAVICA ConsiderationsDierentdiagnosticcriteriahavebeenusedtodeÞnemanic/hypomanicanddepressivepresentations(mixedepisodesormixedfeatures).AlltheguidelinesincludedlackofstrengthintheAGREEIIapplicabilitydomain.ThequalityoftheBritishA

ssociationforPsychopharmacologyguidelineswasthebest,buttheWorldFederationofSoci-etiesofBiologicalPsychiatryguidelinesrepresentedthemostfocusedguidelinesonthetreatmentofmixedstates.TheStahlandcolleaguesguidelinesweretheÞrstonestoaddressdepressionwithDSM-5mixedfeatures,buttherigorofdevelopmentwasinconsistent.Theavailableevidenceonthetreatmentofmixedpatientshadbeengenerallyextrapolatedfromorpooledanalysesofrandomizedclinicaltrials.TheÞndingsofthiscriticalsystematicreviewshouldbekeptwithcautionasthegeneralizabilityoftheseresultsmightbepartlysuitableforthetreatmentofmaniawithmixedfeaturesbutarelesslikelyapplicabletothetreatmentofdepressionwithmixedfeatures.Bipolardisorder(BD)isaseverechronicmooddisorderbroadlyclassiÞedaccordingtothelongi-tudinalcourseinBDtypeI(BDI)ortypeII(BDII)andcharacterizedbyepisodesofmania,hypomania,andalternatingorintertwiningepi-sodesofdepressionwiththepresenceofsubthresh-oldsymptomsbetweentheepisodes(1).AcomplexandquitefrequentpresentationofBDisrepre-sentedbytheoccurrenceofmixedstates,histori-callydeÞnedasthecoexistenceofdepressiveandmanicsymptoms(2).TheidentiÞcationofmixedfeaturesinBDandmajordepressivedisorder(MDD)isanopenchal-lengeinpsychiatryasanaccuratediagnosisisapre-requisitefortheinitiationofadequatethera-peuticapproaches(35).ThemixedepisodewasdeÞnedbyjuxtaposedfullmanicanddepressiveepisodesinthediagnosticandstatisticalmanualofmentaldisorders-IV-textrevision(DSM-IV-TR)(6).AwithmixedfeaturesspeciÞer(MFS)hasbeenincorporatedintheDSM-5(7);thisspeciÞermaybeappliedtomanicepisodesinBDI,hypo-manicepisodesinBDIandBDII,andtomajordepressiveepisodes(MDE)experiencedinBDI,BDII,BDnototherwisespeciÞed(BD-NOS)aswellasinMDD(8).Asaconsequence,hypomanicsymptomscouldcurrentlydenotebothMDDorBDandmanyindividualsalongthemooddisor-dersspectrumthatwerepreviouslyorphansofadiagnosiscouldbeclassiÞedaccordingtoamixed-dimensionalapproach(8,9).Approximately3040%ofmajoraectiveepi-sodesthatoccuroverthecourseofBDappeartoexhibitmixedfeatures(1012).MajorconcernsstillexistfortheDSM-5MFS.Infact,ithas100%speciÞcitybutonly5.1%sensitivity(5).SpeciÞcityattheexpenseofsensitivitysuggeststhatupto95%ofpatientspresentingwiththeMFSaccordingtotheDSM-5arewronglydiag-nosedashavingpureaectiveepisodes(i.e.,withoutmixedfeatures)(5,9).TheDSM-5work-groupexcludedoverlappingsymptomssuchasdistractibility,irritability,andpsychomotoragita-tion,arguingthattheymaylacktheabilitytodif-ferentiatebetweenmanicanddepressivestates(13),inthechoiceofamorespeciÞcapproachattheexpensesofthesensitivityoftheclassiÞcation(8,9).Nevertheless,whencriteriathatconsideroverlappingsymptomsforthediagnosisofmixedfeaturesareused,amorebalancedtrade-obetweensensitivityandspeciÞcitywasobtained,withaspeciÞcityof87%andasensitivityashighas55%(5,14).Inaddition,itisnotclearwhichcouldbetheimplicationontheprevalenceofmixedepisodesoftheDSM-5MFSincomparisonwithpreviousDSMclassiÞcations,asliteratureÞndingsarecon”icting.InBD,DMS-5mixedfea-turesrateswerefoundtobethreefoldhigherthanDSM-IV-TRmixedepisodesinaretrospectivenaturalisticstudy(15)whiletheBipolarCHOICE,arandomizedcomparativeeectivenesstrial,reportedthatfewerpatientssueringfromBDmetmixedcriteriawiththeDSM-5nonoverlap-pingdeÞnitioncomparedtotheDSM-IV(16).Inthemulticenter,multinationalcross-sectionalbipolardisorders:ImprovingDiagnosis,GuidanceandEducation(BRIDGE)-II-MIXstudy,7.5%oftheentiresamplefulÞlledDSM-5criteriaforMDEwithmixedfeatures,butwhenabroaderdeÞnitionincludingoverlappingsymptomswasapplied,theratesofdepressivemixedstateswereashighas29.1%(17).TheDSM-5doesnotprovideaclearrationalefornotweighingcertaindepressivesymptoms,Verdolinietal. suchasweightlossorweightgain,decreasedorincreasedappetite,andinsomniaorhypersomniafortheestablishmentofaMFSinthecontextofmania(orhypomania)eventhoughvirtuallyeverysymptomofdepressionmayco-occurinacute(hypo)manicepisodes(18).ManypatientswithMDEandmixedfeaturesalsopresentwithmani-festationsofanxietythatarenotcapturedbytheMFS(18)aswellasotherclinicalfeatures,thatis,aggressivenessthathavebeenrecentlyfoundtob

eapossiblepsychopathologicalindicationofanunderlyingmixedstate(19).Arecentstudyidenti-Þedthatafour-orÞve-symptomclustercomposedbytheDSM-5MFSsymptomsracingthoughts,increasedtalkativenessanddecreasedneedforsleepandbythetwonon-speciÞcsymptomsdis-tractibilityandirritability,wasshownatbaselineinaplacebo-controlledtrialinvolvingpatientswithMDDwithmixedfeatures(20).Hence,ithasbeenhypothesizedthatthesymptomsoftheDSM-5MFSarethemselvesnon-speciÞc(21).TheintroductionofacodablediagnosticentitydeÞnedaccordingtotheMFSshouldpro-videarationalefortheselectionofdistinctther-apeuticstrategies(9).Nonetheless,nodrugtreatmenthasbeenapprovedbymajorregula-toryagenciesforthemanagementofaectiveepisodeswithaMFS(22).Thetreatmentofmixedepisodesisanimportantchallengeforpsychiatristsastheavailableevidenceisunder-minedbythemethodologicallimitationsofpre-viousRCTs.Generally,theresponsetopharmacologicalagentsofpatientspresentingamanicepisodewithdepressivemixedsymptomshadbeenextrapolatedfromposthocorpooledanalysesofRCTsevaluatingtreatmentresponseinmania(23).Inaddition,thesestudiesgener-allydidnotprovidedataforthemixedsub-group(22).TheevidenceformixeddepressionisevenmorescantaspatientspresentingmixedsymptomsaregenerallyexcludedbydepressionRCTs(24).Asaconsequence,thegeneralizabil-ityoftheresultsofpreviousRCTmaybepartlysuitableforthetreatmentofmaniawithmixedfeaturesbutarelesslikelyapplicabletothetreatmentofdepressionwithmixedfeatures(25).ThetreatmentofmixedstatesrepresentedanunmetneedinpreviousinternationalguidelinesofBD.Indeed,cliniciansshouldfollowexistingguidelineswrittenforthetreatmentofMDDorBDwithfewindicationsforpatientspresentingwithmixedsymptomsinspiteofthehighfre-quencyandclinicalsigniÞcanceofmixedstatesoverthecourseofmooddisorders(26).Onlyrecently,theWorldFederationofSocietiesofBiologicalPsychiatry(WFSBP)publishedguidelinesfortheacuteandlong-termtreatmentofmixedepisodesinBDI(22)andtreatmentguideli-nesaddressingtheDSM-5MFSduringaMDEhavealsobeendeveloped(5).TheFloridaBestPracticePsychotherapeuticMedicationGuidelinesforAdultsWithMajorDepressiveDisorder(27)andtheKoreanMedicationAlgorithmProjectforBipolarDisorder:ThirdRevision(28)speciÞcallyaddressedthetreatmentofmixedfeatures.Inaddi-tion,theavailableupdatededitionsoftheinterna-tionalguidelinesforBDreportedrecommendationsforthetreatmentofmixedepi-sodesandmixedsymptoms.AimsofthestudyAsmixedfeaturesrepresentachallengeforclini-ciansatthediagnostic,classiÞcation,andpharma-cologicaltreatmentlevels,theaimofthisworkwastosummarizeavailableevidenceandtoprovideacomprehensivereviewofrecentlyupdatedguide-lines.Thisworkwaspartofasystematicreviewprotocolofcurrenttreatmentguidelinesformooddisorders,andthisparticularstudyfocusedexclu-sivelyonthetreatmentofmixedstatesandsymp-toms.Acriticalapproachhasbeenappliedtoidentifyareasofconsensusandcontroversy,tounderlinethestrengthsandlimitationsofavailableevidence,andalsothemethodologicalqualityofinternationalguidelinesthatprovidedevidenceforthemanagementofmixedstatesinthecontextofbipolardisorderandmajordepressivedisorder.Finally,unmetneedswereidentiÞedtoprovidedirectionforfurtherresearch.ThissystematicreviewfollowedtheReportingItemsforSystematicReviewsandMeta-(PRISMA)statement(29).AstudyprotocolwasregisteredwithPROSPEROandaprioriSearchstrategyTheMEDLINE/PubMedandEMBASEdata-basesweresearcheduptoMarch21st,2018.DetailedsearchstringsareprovidedintheSup-portingInformationthataccompaniestheonlineversionofthisarticle.Thissearchstrategywasaugmentedthroughhand-searchingofthereferencelistsofincludedarticles.DuplicatepublicationswereidentiÞedandcross-referencedtooptimizeinformation.Twoindependentreviewers(NVandDHM)screenedthetitle/abstractsofretrievedreferencesforMixedstatesandfeaturestreatmentreview eligibility,evaluatedthefull-textsofpotentiallyeli-giblearticles,performedthemethodologicalassessmentofguidelines,andextractedpre-estab-lishedrelevantinformation.Disagreementswereresolvedthroughconsensus,andathirdinvestiga-torwasconsultedwheneveraconsensuscouldnotbeachieved(AM).EligibilitycriteriaInternational

guidelinesforthetreatmentofmixedepisodes,manic/hypomanic(inBDI,BDII,andBD-NOS),ordepressiveepisodes(inBDI,BDII,BD-NOS,andMDD)withmixedfeaturespublishedinanylanguagewereconsid-eredforinclusion.TheInstituteofMedicinedeÞnitionofguideli-nesasstatementsthatincluderecommendationsintendedtooptimizepatientcarethatareinformedbyasystematicreviewofevidenceandanassess-mentofthebeneÞtsandharmsofalternativecareoptions(30)wasconsideredasanoperationalcri-teriatodeÞneincludedguidelines.InternationalguidelinesweredeÞnedasguideli-nesperformedby:(i)aninternationalorganiza-tion,representingmorethanasinglecountry;(ii)apanelofexpertsfromdierentcountries;(iii)anationalorganizationprovidingthatexpertsfromatleastthreedierentcountriesparticipatedinthedevelopmentoftheguideline.OnlyguidelinesforBDupdatedfrom2011onwardshavebeenconsideredinthiscriticalreviewsinceguidelinespublishedbeforethosedateshavebeencriticallyexaminedelsewhere(3133).AsforguidelinesforMDD,onlythoseguideli-nesupdatedfrom2013(whentheMFShasbeenintroduced)havebeenconsidered.Guidelineswereincludediftheyclearlyoutlinedtheirdevelopmentandtheclinicalrecommenda-tionsprocedures.Whenavailable,tablesand/oralgorithmsofmedicationphaseswereconsulted.DataextractionThefollowinginformationwasextractedforeacharticlewhenavailable:internationalorganization;publicationyear;dateofthelastsearch;evidencecategoryoftreatmentoptions;gradingofsafetyandtolerability.Treatmentrecommendationswerereportedfor(i)mixedepisodesaccordingtoDSM-IV-TRand(ii)mixedfeaturesaccordingtoDSM-5.Whenavailable,dataconcerningbothacuteandlong-termtreatmentweredescribedandtreatmentoptionswerespeciÞedforthedepressiveormanicpolaritiesofmixedepisodesorfeatures.Asforecacyevidence,treatmentoptionswerecategorizedintoÞrst-line,second-line,andnotrec-ommendedtreatmentsinaccordancewithanadap-tationofproceduresdescribedelsewhere(31).Thecategoryofevidence(CE)describingthelevelofecacywasspeciÞedforeachtreatmentoptioninTableS1oftheSupportingInformationthataccompaniestheonlineversionofthisarticle.SpeciÞcationsonsafetyandtolerabilityissueswerealsoextrapolatedwhenavailable.Ingeneral,butnotinalltheincludedguidelines,safetyandtolera-bilityaspectswereintegratedwiththeCEassignedtoeachcompoundleadingtodierentrecommen-dationgrades(RG).Inthepurposeofthiscriticalreview,wecreatedanoperationaldeÞnitionofÞrst-andsecond-linetreatmentrecommendations,groupingtheRGofthedierentguidelines(seeTableS2).MethodologicalqualityassessmentThemethodologicalqualityassessmentofincludedguidelineswascarriedoutwiththeAppraisalofGuidelinesforResearchandEvaluation(AGREE)IItool(34).TheAGREEIIwasdesignedtopro-videaframeworktoassessthequalityofguidelinesjudgingthemethodsusedfordevelopingtheguide-lines,thecomponentsoftheÞnalrecommenda-tions,andthefactorsthatwerelinkedtotheiruptakeonthebasisofsixdomains(i.e.,scopeandpurpose,stakeholderinvolvement,rigorofdevel-opment,clarityofpresentation,applicability,andeditorialindependence).AnelectronicgroupappraisalwascreatedattheMyAGREEPluswebsite(35),andaftersuccess-fullycompletingtrainingmodules,thetworeview-ers(NVandDHM)undertookindependentappraisalsforeachoftheincludedguidelines.Thescoresratedbythetworeviewersforthe23itemsoftheAGREEII,forthesixdomains,andfortheoverallqualityoftheguidelinewerecalculatedandscaledaccordingtotheAGREEIIscoringinstruc-SystematicsearchresultsTheinitialsearchreturned7622hits(FigureS1).Followingremovalofduplicates,thetitle/ab-stractsof5280referenceswerescreenedforeligi-bility,and5261referenceswereexcluded.Thefulltextsof19referencesconcerningstructuredtreatmentalgorithmsand/orguidelinessuggestedbyocialpanelswerescrutinizedindetailforeligibility.Amongthem,13referenceswereVerdolinietal. excludedwithreasons(seeTableS3).TheÞnalselectionyieldedsixarticles.ContentresultsEvidenceofecacywassummarizedinTable1(acutetreatment,Þrst-line),Table2(acutetreat-ment,second-line),Table3(maintenancetreat-ment),andTableS4(notrecommendedtreatment).EvidenceofefficacyEvidence-basedguidelinesfortreatingbipolardisor-der:revisedthirdeditionrecommendationsfro

mtheBritishAssociationforPsychopharmacology.BAPupdatedpreviousguidelines(26)andpro-videdthisthirdrevisionbasedonthebestnewavailableevidencefromRCTsandobservationalstudiesemployingquasi-experimentaldesigns(36).TheGradingofRecommendationsAssessment,DevelopmentandEvaluation(GRADE)approach(37)wasusedtogradetherecommendationsandwaspreferredtothetraditionalevidencecategories(38)asthisapproachdowngradednon-experimen-taldescriptivestudiesinfavorofanyRCT,evenofsmallclinicaltrialswherebiaswashighlylikely.Thestrengthoftheevidencewasinsteadratedonthebasisoftraditionalevidencecategories(38)andmayrelatetobothRCTandobservationalÞndings.Alongwiththegradingofastrategyorindividualtreatment,theBAPprovidedrecom-mendationsthatwerenotbasedonsystematicevi-dencebutrepresentedanimportantpracticalorethicalconsensusbetweentheauthorsthatcouldin”uencepractice(StandardofCare,S).CanadianNetworkforMoodandAnxietyTreatments(CANMAT)/InternationalSocietyforBipolarDisor-ders(ISBD)2018guidelinesforthemanagementofpatientswithbipolardisorder.TheCANMATincollaborationwiththeISBDupdatedtheguidelines,andtheevidenceratingshavebeenmodiÞedfromthepreviouseditionstoincreaserigor(39).AÞnalgradingofrecommendationsintoÞrst-,second-,orthird-linewaslisted,andanewhierarchicalorderoftreatmentswascreatedforÞrst-andsecond-linerec-ommendations,consideringlevelsofevidenceforecacyofeachtreatment,aswellasacuteandmaintenancesafetyandtolerabilityandriskoftreatmentemergentswitch.Inthesectionsdedicatedtotheacuteandlong-termmanagementofbipolarmania/hypomaniaanddepression,theauthorsreportedaboutthenewmixedfeaturespeciÞerinthespeciÞcsectionaboutclinicalfeaturesthathelp Table1.Comparisonoftheincludedguidelines:evidenceofefficacy,acutetreatment,firstlineFirstlineGuidelinesMania/hypomaniawithmixedfeaturesormanicmixedepisodeDepressionwithmixedfeaturesordepressivemixedepisodeMonotherapyBAP3rdeditionOralSGA(I)CANMAT/ISBD2018SGA:ASN,ARP,OLZandZPD(1)SGA:LUR(2)CINP-BD-2017RANZCPMoodDisordersCPGSGA:OLZ,QTPMS:VPAMixeddepressionguidelinesSGA:LUR,ASN,QTP,QTP-XR,ARPandZPD(1);OLZandCAR(2)MS:LMT,VPAandLi(2)WFSBPMixedstatesSGA:OLZ(A,forManS),ARP(B,forManSandDepS)andPLP(B,forManS)CombinationBAP3rdeditionCLZLiorMSintreatmentresistantpatientsCANMAT/ISBD2018SGAVPA:ASN(2),ARP(2),OLZ(1)LURLi/VPA(1)OFC(2)CINP-BD-2017OLZMS(2)OLZMS(2)RANZCPMoodDisordersCPGSGA(ASN,OLZ,ARP,ZPD,RPD)MS(II)SGA(OLZ,QTP)orVPAAD(II)VPAOLZ(II)MixeddepressionguidelinesMS(Li,LMT,VPA)VPAVPAWFSBPMixedstatesOLZVPA(AforManSandDepS)MS(BforDepS)TAUAD,antidepressants;ARP,aripiprazole;ASN,asenapine;BAP,BritishAssociationofPsychopharmacology;BD,bipolardisorder;BDZ,benzodiazepines;CANMAT,CanadianNet-workforMoodandAnxietyTreatment;CAR,cariprazine;CINP,InternationalCollegeofNeuropsychopharmacology;CLZ,clozapine;CPG,clinicalpracticeguidelines;DepS,depres-sivesymptoms;ISBD,InternationalSocietyofBipolarDisorder;ManS,manicsymptoms;Li,lithium;LMT,lamotrigine;LUR,lurasidone;OFC,olanzafluoxetine;OLZ,olanzapine;PLP,paliperidone;QTP,quetiapine;RANZCP,RoyalAustralianandNewZealandCollegeofPsychiatrists;RPD,risperidone;SGA,secondgenerationantipsychotics;TAU,treatmentasusual;VPA,valproate;WFSBP,WorldFederationofSocietiesofBiologicalPsychiatry;ZPD,ziprasidone;XR,extended-release.(I),(1),(A),firstcategoryofevidence;(II),(2),(B),secondcategoryofevidence.Mixedstatesandfeaturestreatmentreview directtreatmentchoices.Unfortunately,thetaskforcedidnotgradetheecacyoftreatmentsforacuteandlong-termmanagementofmixedfeaturesduringbipolarmaniaanddepressionbutonlyforhypomania.TheauthorsofthissystematicreviewdecidedtoextrapolatetheCEformixedfeaturesfromthecorrespondingbipolarmaniaanddepres-sionrecommendations.TheInternationalCollegeofNeuro-Psychopharmacol-ogytreatmentguidelinesforBipolardisorderinadults(CINP-BD-2017).TheCINPrecentlyproposedtheÞrsteditionofthetreatmentguidelinesforpatientswithBDIorBDIIinprimaryandsec-ondarycareandaddressedthetreatmentofadultpatientswithmixedfeatures,rapidcycling,andpsychoticfeaturesbutnotchildren,adolescents,ortheelderly(40).Theauthorsrevieweddatafromclinicaltrialsa

ndmeta-analyses,reservedtheprivi-legetojudge,andusedatafromopentrials,reviews,andopinionlettersonanindividualbasis,accordingtotheirresearchandclinicalexperience,tookintoconsiderationguidelinesdevelopeddur-ingthelast10years,andrecommendationswerestatedbyconsensusthroughtheDelphimethod.Theworkgroupdecidedtodevelopagradingmethodfortheevaluationofavailabledata,whichisanadaptationoftheGRADE.Afterthegradingofdataandinterventions,theauthorscreatedaprecisealgorithmforexperimentalreasonsandÞnallyestablishrecommendations.Asformixedstates,theworkgroupstatedthatdatasuggestedthatmixedfeaturesrespondtotreatmentinadierentwaythanDSM-IV-TRmixedepisodes.Theworkgroupseparatelypro-videdeectsonthemanicandthedepressivecom-ponentofmixedepisodesofthemostimportantRoyalAustralianandNewZealandCollegeofPsychi-atristsclinicalpracticeguidelinesformooddisorders(MoodDisordersCPG).TheRANZCPdevelopedtheMoodDisordersClinicalPracticeGuideline(MoodDisordersCPG)aspartoftheRANZCPCPGProject20132015(41).TheMoodDisorderCPGistheÞrstClinicalPracticeGuidelinetoaddressbothMDDandBD,coherentlywiththeconceptualizationofamoodspectrum.Thelevels Table2.Comparisonoftheincludedguidelines:evidenceofefficacy,acutetreatment,secondlineSecondlineGuidelinesMania/hypomaniawithmixedfeaturesormanicmixedepisodeDepressionwithmixedfeaturesordepressivemixedepisodeMonotherapyBAP3rdeditionLMT(IV)CANMAT/ISBD2018ZPD(3)formixedhypomaniaCINP-BD-2017SGA:ARP,ASN,PLP,RPD,OLZ(3),andZPD(4)MS:VPA,CBZ(3)OFC(4)SGA:ARP,ASN,OLZ(3),andZPD(4)MS:VPA(4),CBZ(3)OFC(4)RANZCPMoodDisordersCPGMixeddepressionguidelinesMS:CBZ(3)WFSBPMixedstatesSGA:ASN(CforDepS),RPD(C),CAR(CforManS),CLZ(CforManS),OLZ(CforDepS),ZPD(CforManSandMS:VPA(CforManS),CBZ(CforManSandDepS)SGA:LUR,OLZ(C)MS:CBZ(CforDepS)CombinationBAP3rdeditionECT(IV)CANMAT/ISBD2018ASN(4)RANZCPMoodDisordersCPGECT(III)MixeddepressionguidelinesLi(3)pramipexole(3)ECT(3)MS:(Li,LMT,VAP)orSGAbupropionorSSRIorMAOI(3)WFSBPMixedstatesSGA:QTP(CforManS),CLZ(CforManS),MS:OXC(Li,CforManS),GBP(C,forManSandDepS),TPR(DforManS)ECT(CforManSandDepS)ECT(C)AD,antidepressants;ARP,aripiprazole;ASN,asenapine;BAP,BritishAssociationofPsychopharmacology;BD,bipolardisorder;CANMAT,CanadianNetworkforMoodandAnxi-etyTreatment;CBZ,carbamazepine;CAR,cariprazine;CINP,InternationalCollegeofNeuropsychopharmacology;CLZ,clozapine;CPG,clinicalpracticeguidelines;DepS,depres-sivesymptoms;ECT,elettroconvulsivetherapy;FGA,first-generationantipschotics;GBP,gabapentin;ISBD,InternationalSocietyofBipolarDisorder;ManS,manicsymptoms;OXC,oxcarbazepine;Li,lithium;LMT,lamotrigine;LUR,lurasidone;MAOI,monoamineoxidaseinhibitor;OFC,olanzapinefluoxetine;OLZ,olanzapine;PLP,paliperidone;QTP,que-tiapine;RANZCP,RoyalAustralianandNewZealandCollegeofPsychiatrists;RPD,risperidone;SGA,second-generationantipsychotics;SSRI,selectiveserotoninreuptakeinhibi-tor;TAU,treatmentasusual;TPR,topiramate;VPA,valproate;WFSBP,WorldFederationofSocietiesofBiologicalPsychiatry;ZPD,ziprasidone;XR,extended-release.(III),(3),(C),thirdcategoryofevidence;(IV),(4),(D),fourthcategoryofevidence.Verdolinietal. ofevidencewereassignedandadaptedfromtheAustralianNationalHealthandMedicalResearchCouncil(NHMRC)levelsofevidenceforinterven-tionstudies(42).TheMoodDisordersCPGgavetwotypesofrecommendations:(i)Evidence-basedrecommendations(EBRs)formulatedwhenevi-dencefrominterventionstudieswassucientandconsistenttosupportarecommendationonagiventopic.ForeachEBR,strengthofevidencewasratedusingtheNHMRClevelsofevidence.(ii)Consensus-basedrecommendation(CBR),derivedthroughdiscussionandagreementwithintheworkgrouponspeciÞcaspectsofmooddisorderswhosenatureandmanagementareincomplete.Aslittleisknownaboutthediagnosisandtreat-mentofmixedfeaturespresentationsasdeÞnedbyDSM-5(Malhi,2013,2014),theauthorsconcludedthattreatmentguidelinesformixedfeaturesrelyheavilyonclinicalexperienceandconsensusrec-Guidelinesfortherecognitionandmanagementofmixeddepression.Asstatedbytheworkgroup,oneofthemostimportantchallengesderivedbythenewDSM-5MFSistooptimizethetreatmentforpatientswithdepressionexhibitingconcomit

antsubthresholdhypo/manicfeatures(43).Withthisaiminmind,apanelofexpertsonmooddisordershasbeenassembledtodevelopguidelinesontherecognitionandtreatmentofmixeddepressionmadeinreferencetoDSM-5.TheWorldFederationofSocietiesofbiologicalpsychi-atryguidelinesforthebiologicaltreatmentofbipolardisorders:acuteandlong-termtreatmentofmixedstatesinbipolardisorder.Theinternationaltask-forceoftheWFSBPdevelopedthispracticeguidelinespeciÞcallyforacuteandmaintenancepharmacologicaltreatmentandpreventionofmixedepisodesinBD(22).Consideringthetopicofthiscriticalreview,wedecidedtoincludethisbrand-newguidelineaboutmixedepisodesandtoexcludepreviousguidelinesfromthesametask-forceaboutacutemania(23),bipolardepression(44),andmaintenancetreatmentofBD(45).Theauthorsdistinguishedtherecommendationsforthefollowingcategories:(i)treatmentofacutemanicmixedepisodes;(ii)treatmentofacutedepressivemixedepisodes;(iii)maintenancetreat-mentafteranacutemixedepisodeinpreventingepisodesofanypolarity;(iv)maintenancetreat-mentafteranacutemanicordepressedepisodeinpreventingnewmixedepisodes.TherankingofevidencewasthesameusedinthedevelopmentofotherguidelinesoftheWFSBP(46).Categoriesofevidence(CE)AorB,corre-spondingtoRG13,weredeÞnedfortreatmentsthathaveshowntheirecacyindouble-blind Table3.Comparisonoftheincludedguidelines:evidenceofefficacy,maintenancetreatmenttreatmentGuidelinesMania/hypomaniaordepressionwithmixedfeaturesormanicordepressivemixedepisodeMonotherapyBAP3rdeditionMS:Li(I)CANMAT/ISBD2018QTPinpreventingepisodesofanymoodepisode,ofdepressionandmania,firstlineCINP-BD-2017SGA:OLZ(1)RANZCPMoodDisordersCPGVPALi;CBZ?MixeddepressionguidelinesThesameeffectiveacutetreatmentWFSBPMixedstates1.Afteranacutemixedepisodeinpreventingepisodesofanypolarity,firstline.Li(Bformanicandforanytypeofepisode),OLZ(B),QTP(B,formanic,depressiveandanytypeofepisode)2.Afteranacutemixedepisodeinpreventingepisodesofanypolarity,secondline.ZPD(C,formanicrelapse)3.Afteranacutemanicordepressedepisodeinpreventingnewmixedepisodes,firstline.VPA(B)4.Afteranacutemanicordepressedepisodeinpreventingnewmixedepisodes,secondline.Li(D)orOLZ(D)CombinationBAP3rdeditionCANMAT/ISBD2018QTPLi/VAPinpreventingepisodesofanymoodepisode,ofdepressionandmania,firstline.CINP-BD-2017ARPMS(2)RANZCPMoodDisordersCPGMixeddepressionguidelinesADWFSBPMixedstates1.Afteranacutemixedepisodeinpreventingepisodesofanypolarity,firstline.QTPLiorVPA(Aformanic,depressiveepisodeandanytypeofepisode)orECT(C)2.Afteranacutemixedepisodeinpreventingepisodesofanypolarity,secondline.RPD(C),ARPLMT(C,fordepressiveepisodes)3.Afteranacutemanicordepressedepisodeinpreventingnewmixedepisodes,firstline4.Afteranacutemanicordepressedepisodeinpreventingnewmixedepisodes,secondlineAD,antidepressants;ARP,aripiprazole;ASN,asenapine;BAP,BritishAssociationofPsychopharmacology;BD,bipolardisorder;CANMAT,CanadianNetworkforMoodandAnxi-etyTreatment;CBZ,carbamazepine;CINP,InternationalCollegeofNeuropsychopharmacology;CLZ,clozapine;CPG,clinicalpracticeguidelines;ECT,elettroconvulsivetherapy;ISBD,InternationalSocietyofBipolarDisorder;Li,lithium;LMT,lamotrigine;OLZ,olanzapine;QTP,quetiapine;RANZCP,RoyalAustralianandNewZealandCollegeofPsychia-trists;RPD,risperidone;SGA,secondgenerationantipsychotics;VPA,valproate;WFSBP,WorldFederationofSocietiesofBiologicalPsychiatry;ZPD,ziprasidone.(I),(1),(A),firstcategoryofevidence;(II),(2),(B),secondcategoryofevidence;(III),(3),(C),thirdcategoryofevidence;(IV),(4),(D),fourthcategoryofevidence.Mixedstatesandfeaturestreatmentreview placebo-controlledstudies.Lowerlevelofevidencewasrecordedforopenstudies(CEC)orcon”ict-ingresults(CED)(lowRG4or5respectively).DeviationsfromtheoriginalWFSBPguidelinegradingsystemweretheroleofposthocandsub-groupanalysesaswellaslargeregistrystudies.Asposthocanalyses,whenthestudyincludedintheanalysesplantheposthocanalysisanditwassucientlypowered,aCEBwasconsid-ered.Ifitwasnotthecase,alowerCEwasassigned(CEC).Asforregistrystudies,atleastaCEClevelwasattributedtoregistrystudies(asotherretrospectivestudies)ofgoodqualityandminimizedr

iskofbias.ThetreatmentofunipolarMDEwithmixedfea-turesaccordingtoDSM-5wasnotconsideredinthisguideline.Whenavailable,theauthorsconsid-eredresultsfromstudiesinBDIIandrapidcyclingpatientsaswellasinformationforecacyorsafetyinchildrenoroldage.SafetyandtolerabilityTheCINP-BD-2017(47)andtheWFSBPguideli-nes(22)gradedeachmedicationintermsofsafetyandtolerabilityandconsideredtheseaspectsinRG.TheCANMAT-ISBD(39)task-forceconsid-eredsafetyandtolerabilityconcernsandrisksoftreatmentemergentswitchinmania/hypomaniaordepressioninprovidingRGprovidingratingsreachedbyconsensus(seeTableS2).TheBAP(36)didnotintegratesafetyandtoler-abilityaspectswithCEtoprovideRG.TheMoodDisorderCPG(41)bytheRANZCPdidnotcon-sidersafetyandtolerabilityinthedevelopmentofRG,buttheauthorsprovidedÞguresbasedonexpertpanelaverageratingsinwhichtheygraphi-callyreportedtheratingsoftolerabilityforthedif-ferentcompounds.Stahlandcolleagues(43)reportedaboutsafetymonitoringintheirguidelinesforthetreatmentofmixeddepression,butitisnotclearwhethertheyintegratedtheseaspectsintheRG.Theydevelopedatableaboutthenotableside-eectsassociatedwithMSandaÞgurefortherelativetolerabilityofSGA(forsedation,weightgain,extrapyramidalsymptoms)(seeTable4).QualityoftheincludedguidelinesThemethodologicalqualityassessmentofincludedguidelinesconductedbythetwoindependentreviewersisreportedintheTableS5.ThequalityscoresofthespeciÞcdomainsforeachguidelineobtainedbythetwoappraisersarereportedinTable5.Thequalitysubstantiallydieredamongtheincludedguidelines.TheAGREEIIoverallassessmentraterangedbetween42%and92%.TheBAPguidelinesreachedthehighestAGREEIIoverallassessmentrate.SummaryofthetreatmentrecommendationsThesixguidelinesincludedinthissystematiccriti-calreviewprovideddierentrecommendationsforthetreatmentofmixedstatesorfeaturesofaec-tiveepisodes.Thiscouldbetheconsequenceofdif-ferentapproachestoratethequalityofavailableevidence.Fourofsixguidelines(22,39,40,43)providedsomegradingofsafetyandtolerability,withtreatmentrecommendationsbasedonacom-binationofecacyandrisk/beneÞtratio.Wedis-cussedeachcompoundaccordingtoanoperationaldeÞnitionofÞrst-orsecond-linetreat-mentrecommendationsaswellaseachtreatmentoptionisprovidedwiththespeciÞcationoftheRGdeÞnedaccordingtotheoriginalguidelines(seeTableS2).Ingeneral,theguidelinesrecommendedstartingthetreatmentwithamedicationfulÞllingthehigh-estcriteriaforecacyandtolerability,thatisSGAsincombinationwithlithiumorvalproateshouldbereservedformoreseverepresentationsasÞrst-linechoiceorasasubsequentstepwhenanotherÞrst-linemedicationfailed.Mood-stabiliz-ingmedicationsgenerallyreachedevidenceforthelong-termtreatment.Alltheguidelinesagreeduponavoidinginmixeddepression,inbothBDandMDD,theuseofADoratleasttocombineaMStotheongoingADtreatment.Mania/hypomaniawithmixedfeaturesormanicmixedepisodes.Oralantipsychotics,bothdopamineantagonistsandpartialagonists,weretheÞrst-linewasrecommendedasÞrst-linechoiceinthetreatmentofacutemania/hypomaniawithmixedfeaturesinalleligibleguidelineswiththeexceptionofthelastCANMAT/ISBDguideline(2).Inparticular,theWFSBPrecommendeditinmonotherapywithRG2formanicsymptomsbut4fordepressivesymptomsduringamanicmixedepisodeinthecontextofBD.ThecombinationofolanzapinewithaMSwasrecommendedasÞrst-linetreatmentintheRANZCP(II),bytheCINP(2)andbytheWFSBP(2forvalproate).Olanzap-ineinmonotherapywasgradedas3bytheCINP.DespitetheCEforolanzapinewasrated1intheCANMAT/ISBDguidelines,bothforthemonotherapyandthecombinationtreatmentwithVerdolinietal. Table4.Comparisonoftheincludedguidelines:gradingofcompoundsaccordingtosafetyissuesandtolerabilityBAP3rdeditionCANMAT/ISBD2018*CINP-BD-2017RANZCPMoodDisordersCPGMixeddepressionguidelinesWFSBPMSGradingforSTprovidedNoYesYesNoNoYesIntegrationofSTwithCEtoprovideRGNoYesYesNonkYes,L0AripiprazoleA1A0,LAsenapineACarbamazepineA,L0CariprazineAClozapine3ECTAEscitalopram1Fluoxetine1HaloperidolAImipramine2LamotrigineALamotrigine(adj)ALithiumALurasidoneAOlanzapineAOxcarbazepine1PaliperidoneA1A0,L0Paroxetine1QuetiapineA1A0,LRisperidoneA1A0,LRisperidoneLAIARisperidoneLAI(adj)ASertr

aline1Topiramate3Tranylcypromine2ValproateAVenlafaxine2ZiprasidoneACombinationtherapiesLithium/ValproateALithium/ValproateALithium/ValproateALithium/ValproateALithium/ValproateAMixedstatesandfeaturestreatmentreview valproate,olanzapinewasconsideredasasecond-linetreatmentbecauseofthesafetyandtolerabilityconcerns.Olanzapinehadprobablythebestposi-tiveevidenceofallmedicationfortheacutetreat-mentofBDIpatientswithmanicmixedepisodes.Itshighlevelofevidenceinmonotherapywasjusti-Þedbyresultsfromtwoconsecutiveshort-termRCT(48,49)andfourposthocanalyses,twoana-lyzingsubgroupsoftheabovementionedRCT(50,51),athirdposthocanalysisalsoincludingaJapanesestudy(52)andaposthocanalysisoftheÞrstacutethree-armRCTwithasenapinevs.pla-ceboororalolanzapine(53).Theevidenceofolan-zapineasadd-ontreatmentwasbasedontwoRCT,oneevaluatingthecombinationolanzapine-divalproexvs.divalproexmonotherapy(54)andtheotheronecomparingolanzapineproatevs.placebolithium/valproate(55),andposthocanalysisofthissecondRCT(56).Thecombinationofolanzapinewith”uoxetine(OFC)wasratedas4bytheCINP(47)forinconclusivedataforthemaniccomponentofmixedstates.Despitethis,theCINPgradedOFCasthebestchoiceinthepresenceofafullDSM-IVmixedepi-sode(CINPfourthsteprecommendation).wasrecommendedasaÞrst-linechoiceinmonotherapybytheBAP(I),bytheWFSBP(3),formanicanddepressivesymptoms),bytheCANMAT/ISBD(1)andincombinationwithMSbytheRANZCP(II)andbythe Table4.(Continued)BAP3rdeditionCANMAT/ISBD2018*CINP-BD-2017RANZCPMoodDisordersCPGMixeddepressionguidelinesWFSBPMSLithium/VaproateALithium/VaproateAValproateASSRIs/bupropion(adj)AOlanzapine-fluoxetineAA,acutetreatment;AD,antidepressants;BAP,BritishAssociationofPsychopharmacology;BD,bipolardisorder;CANMAT,CanadianNetworkforMoodandAnxietyTreatment;CE,categoryofevidence;CINP,InternationalCollegeofNeuropsychopharmacology;CPG,clinicalpracticeguidelines;ECT,elettroconvulsivetherapy;FGA,firstgenerationantipsy-chotic;ISBD,InternationalSocietyofBipolarDisorder;L,long-termtreatment;LAI,longactinginjectable;MS,mixedstates;nk,notknown;RANZCP,RoyalAustralianandNewZealandCollegeofPsychiatrists;RG,recommendationgrades;SSRIs,selectiveserotoninreuptakeinhibitors;ST,safetyandtolerability;WFSBP,WorldFederationofSocietiesofBiologicalPsychiatry.*CANMAT/ISBD2018Safety(S)andTolerability(T)ConcernsinAcute(A)andMaintenance(L)treatmentandRisksofTreatmentEmergentSwitchinMania/Hypomania(M/H)orDepression(D)consensusratings:Limitedimpactontreatmentselection;Minorimpactontreatmentselection;Moderateimpactontreatmentselection;cantimpactontreatmentselection;nknotknown.CINP-BD-2017gradingoftreatmentoptionsaccordingtosafetyissuesandtolerability:fromLevel1(verygoodtolerability)toLevel3(poortolerability).Onlymostfrequentlyusedtreatmentsreported.WFSBPMixedstatesSafety&Tolerability(ST)ratingforacute(A)andlong-term(L)treatment:from(bestpositiveevidence)to(strongnegativeevidence);(equallyadvantagesanddisadvantages,orunknown).Cautioninwomenofchildbearingage. Table5.QualityscoresofthesixAGREEIIdomainsandoverallassessmentDomain1Scopeandpurpose(%)Domain2involvement(%)Domain3Rigorofdevelopment(%)Domain4Clarityofpresentation(%)Domain5Applicability(%)Domain6independence(%)assessment(%)BAP3rdedition97678292408392CANMAT/ISBD201889586081357167CINP-BD-201769646678259658RANZCPMoodDisordersCPG72836481339667Mixeddepressionguidelines72472467259242WFSBPMixedstates86507883339283BAP,BritishAssociationofPsychopharmacology;BD,bipolardisorder;CANMAT,CanadianNetworkforMoodandAnxietyTreatment;CINP,InternationalCollegeofNeuropsy-chopharmacology;CPG,clinicalpracticeguidelines;ISBD,InternationalSocietyofBipolarDisorder;RANZCP,RoyalAustralianandNewZealandCollegeofPsychiatrists;WFSBP,WorldFederationofSocietiesofBiologicalPsychiatry.Verdolinietal. CANMAT/ISBDwithvalproate(1).TheCINPratedaripiprazoleinmonotherapyas3.Theposi-tiveevidencefortheserecommendationswasbasedontwoRCTreportedseparatedataformixedpatients(57,58),ontwoRCTwithamixedsampleofmanicandmixedpatients(59,60),anegativeacutestudy(61)andtwounderpoweredRCTs(62,63).Asforthecombinationtreatmen

t,aRCTtestedaripiprazoleincombination/augmentationtherapyinacutemanicandDSM-IVmixedepi-sodesbutdidnotreportseparatedata(64).inmonotherapywasaÞrst-linechoiceformanicsymptomsinacutemixedepi-sodesbytheWFSBP(3)onthebasisoftwodier-ent3-weekRCTs,theÞrstonecomparingecacyinBD-Ipatients,including171mixedpatients,ofextended-release(ER)paliperidonewithquetiap-ineandplacebo(65).ThesecondstudycomparedthreedierentdosagesofER-paliperidone(3mg,6mg,and12mg)withplaceboinpatientswithDSM-IVcriteriaforamanicormixedepisode(163mixedepisodes)(66).TheCINPratedpaliperidoneasasecond-linechoice(3)foracutemixedepisodesonthebasisofthesamestudies.Onthecontrary,paliperidoneincombinationwithlithiumorvalproatewasnotfoundtobesuperiortolithiumorvalproatemonotherapyinaRCTincludingpatientswithamixedindexepisode(67).OtherrelativelynewSGAs,suchas,wererecommendedformania/hy-pomaniawithmixedfeaturesormanicmixedepi-sodesbutwithcon”ictingRGamongthewasrecommendedasaÞrst-linechoiceincombinationwithMS(II)bytheRANZCPandasasecond-linechoiceinmonotherapyformanicanddepressivesymptoms(4)bytheWFSBP,bytheCINP(4),andtheCAN-MAT/ISBD(2,formixedmaniaandhypomania).Thisseemsatoddswiththefourthsteprecommen-dationintheclinicalguidelinesforthetreatmentofacutemania/hypomaniainwhichtheauthorsestablishedthatziprasidonewasbetweenthetwobestchoicesinthepresenceofafullDSM-IVmixedepisode.TheuseofziprasidoneinmonotherapywasjustiÞedbya3-weekRCT(68)andareplicationtrialbyPotkinandcolleagues(69).Unfortunately,thesestudiesdidnotreportseparateddataformanicormixedpatients.ApooledanalysisofthesetwoRCTre-examinedthedataandshowedimprovementinbothmanicanddepressivesymptomatology(70).wasaÞrst-linechoiceinmonotherapyaccordingtotheCANMAT/ISBD(1)andincom-binationwithaMS(particularlyvalproate,CAN-MAT/ISBD1)accordingtotheRANZCP(II).Itwasratedasasecond-linechoiceinmonotherapyfortheacutetreatmentofdepressivesymptoms(butnotmanicsymptoms)ofmanicmixedepi-sodesaccordingtotheCINP(3)andtheWFSBP(4).Therecommendationswerebasedona3-weekRCTvs.placeboandvs.olanzapineasactivecom-parator(53),onthreeposthocanalyses(71obtainedusingthepooleddataofthepreviousRCTandanidenticaldesigned3-weekRCT(74)andfroma3-weekRCTcomparingasenapine5and10mgbidwithplacebo(108of367mixedpatients)(75).Althoughresultswerecon”ictingfortheecacyofasenapineonthemanicsymptomsoftheacutemanicmixedstate,signiÞcantimprovementintheMontgomeryAsbergDepres-sionRatingScale(MADRS)withasenapinebutnotwitholanzapinewasfound,withasenapinedif-ferencingfromtheplacebogroupmoreinthosepatientswithhigherseverityofdepression(73).Inaddition,afurtherposthocanalysisoftwoacuteRCTstudies(53,76)examinedasubgroupof98patientswithamixedepisode,showingsigniÞcantdecreasesinMADRSscoresgreaterintheasenap-inegroupthanintheplacebogroup(77).Afurtherstudyassessedthecombinationofasenapinewithlithiumorvalproatevs.placebo,butnoseparateanalysisformixedpatientshasbeensupplied(78).wasrecommendedasaÞrst-linetreatmentonlyincombination/augmentationtreatmentfordepressivesymptoms(3)andasasecond-linetreatmentformanicsymptoms(4)dur-ingamanicmixedepisodeaccordingtotheWFSBP.Theevidencefortheserecommendationswasbasedon(i)aRCTinhypomanicpatientswithmixedfeaturesreportingthatadjunctivequetiapineissuperiortoadjunctiveplaceboinimprovingoverallseverityanddepressivesymptoms,butnot(hypo)manicsymptoms(79),(ii)aretrospectivestudyofBDpatientsreportingthattheproportionofmixedpatientsrespondingtoquetiapinewas77%(80),and(iii)acasereportofapatientwithmixedBDwithpsychoticfeaturesnotrespondingtothecombinationofvalproate,olanzapine,and”uoxetine,whoafterthereplacementofolanzap-inebyquetiapineimprovedinthemanicandpsy-choticsymptoms(81).Therearefourpositivestudiessupportingtheecacyofquetiapineupto800mg/dayforthetreatmentofacutemaniainmonotherapy(65,8284),buttherewassomecon-cernaboutitsecacyagainstmixedepisodesbecauseofthefollowingreasons:mixedpatientswereexcluded(82,83),asub-analysisforquetiap-inewasnotprovidedasitservedonlyasaninter-nalcomparator(65)whileinthe3-weekRCTinvestigatingextended-releasequetiapine,quetiap-inewasnotbetterthanplaceb

oforimprovingmanicanddepressivesymptoms(84).ArecentMixedstatesandfeaturestreatmentreview study(85)evaluatedtheecacyofquetiapineextendedreleasevs.placeboasconcomitanttreat-menttomoodstabilizersinthecontrolofsub-thresholdsymptomsofBDbutdidnotprovideseparateanalysisforthemixedsubgroupofTheecacyofhasbeeninvestigatedinplacebo-controlledstudies(8688)andintwopooledanalyses(89,90)reportingsigniÞcantposi-tiveresultsforthemixedpatientssubgroup.Thus,theRGforcariprazineinmonotherapyforthemanicsymptomsofanacutemanicmixedepisodeis4(WFSBP).Despitethegoodevidenceforacutemania,didnotreachhighlevelofevidenceinalltheguidelinesforthetreatmentofmixedmanicstatesprobablybecauseoftheriskofswitchtodepressionandthelimitednumberofmixedpatientsinthetrials.TheRANZCPrecommendeditasaÞrst-linetreatmentonlyincombinationwithaMS(II)whileboththeCINPandtheWFSBPrecommendedrisperidoneinmonotherapyasasecond-linetreatment(CINP3;WFSBP4).AmongthefourRCTassessingtheecacyofrisperidone16mg/dayforthetreatmentofacutemanicandmixedepisodes(9193),onerisperidonemonotherapytrialincludingmixedpatients(didnotshowimprovementofmanicsymptomsvs.placebo(91)aswellastherandomizedanddouble-blindhead-to-headcomparisonofrisperidonevs.olanzapine(94)showednosigniÞcantdierencesinmanicanddepressiveimprovement.Asforcom-binationtreatment,risperidonewascomparedwithhaloperidolorplacebo,allincombinationwithlithiumorvalproateinmixedpatients(withnosigniÞcantdierences(95).Asfor,theWFSBPtask-forceidenti-Þedtwosmallstudies,aretrospectivechartreviewexaminingclozapineindysphoricmanicpatientsasmonotherapyorcombinedwithlithium,val-proate,oranAD(96)andanopen-labelstudyenrolling10adolescentswithtreatment-resistantmanic/mixedepisodes,prescribedwithclozapinealoneorincombinationwithaMS(97).Inconsid-erationoftheissuesexistingwithsafety,thetask-forcerecommendedclozapineasasecond-linetreatment(4)foracutemanicmixedepisodesinmonotherapyorcombinationtherapy(MSonly).Similarly,theBAPrecommendedclozapineincombinationwithlithiumoranticonvulsantsasaÞrst-linetreatmentintreatment-resistantpatients.FGA,inparticular,hasbeenstudiedinmixedpatientsmainlyasanactivecomparatorforSGAincombinationornotwithMS(95,98).Nodierencewasfoundbetweenolanzapineandhaloperidolinmonotherapyintermsofratesofsymptomaticremission(YoungManiaRatingScale-YMRSscores)whileinthecomparisonwithrisperidoneincombinationtherapywithaMS(lithiumorvalproate),haloperidolMSwasnotdierentfromimprovementobservedwithplaceboMS,leadingtoarecommendationgradeof4forhaloperidolinmonotherapyforanacutemanicmixedepisode(WFSBP).AsforMS,onlyinmonotherapywasasecond-linetreatmentforbothmanicanddepressivesymptomsduringamanicmixedepi-sodeaccordingtotheWFSBP(C)andtheCINP(3).TheevidencefortheserecommendationswasbasedontwoRCTcomparingtheacuteecacyofextended-releasecarbamazepinevs.placebo(99,100)withimprovementformanic(100)orfordepressivesymptoms(99).Toassessthereliabilityoftheseresults,acombinedanalysispoolingthedatafrombothtrialswasconducted(147)anddemonstratedsigniÞcantimprovementofbothmanicanddepressivesymptomsinmixedpatients(101).Carbamazepineinacutecombinationtreat-menthasneverbeentestedinmixedpatients.inmonotherapywasrecommendedasasecond-linetreatmentaccordingtotheCINP(3)andtotheWFSBP(4,formanicsymptoms).Lim-iteddataconcerningtheecacyofvalproateinacutemixedmaniaexistevenbecausesometimessubgroupanalysesinmixedpatientshaveeithernotbeenconductedorproperlyreported(102,103).Aposthocanalysisofa3-weekRCT(104)didnotÞndanypreferentialeectfordivalproexinclassicvs.mixedmanicpatients(105).Asmallcaseseriestestedvalproateinintravenousinfusioninaveryfewsampleofseverelymanic,mixed,orbipolardepressedpatients(twomanic,twomixed,onemixedwithrapidcycling,twodepressed)withimprovementforthetwomixedpatients(106).Noevidenceexistsforvalproateincombinationther-apyforacutemixedstates.inmonotherapyhasbeenrecom-mendedasasecond-linetreatmentbytheBAP(IV)probablyonthebasisofapossibleextensiontomixedpatientsofrecommendationformanicpatients.Nonetheless,norandomizedcontrolledstudiesinmanicmixedpatientsorsubgroupanaly-sesofst

udiesinacutemaniawithlamotriginehavebeenreported.wasratedas5(second-line)inmonotherapybytheWFSBP.TopiramatehasbeentestedinfourRCTsinacutemaniawithneg-ativeresults(107);hence,noneoftheseRCTsup-pliedasubgroupanalysisforpatientswithmixedstates.Evidencefortopiramateinthetreatmentofacutemixedmaniaderivedfromoneretrospectivechartreview(108),twoopenstudiesthatusedVerdolinietal. topiramateasadjunctivetherapyinpatientsrefrac-torytoothertreatments(109,110)andaretrospec-tivestudyevaluatingadjunctivetopiramateinadolescents(111),reportingpartialimprovementinmanicmixedpatients.havebeenevalu-atedbytheWFSBPandestimatedasasecond-linetreatmentincombinationtherapy(4).Asfor,mixedpatientswithanunsatisfactoryclinicalresponsetolithiumhavebeenadministeredwithadd-onoxcarbazepinewithgoodclinicalresponseinÞveofsixmixedpatients(112).hasbeentestedinmonotherapyina8-weeksRCTindysphoricmania(113)withsuperiorityofgabapentintocarbamazepineinmaniaratingsandtolamotrigineindepressionratingsaswellasimportantshortcomingsindesignandreportinglimitedthereliabilityoftheresults.GabapentinhasbeentestedinÞveopen-labelstudiesasadjunc-tivetreatment(114118)withimprovementinmanic(114,116,117)orindepressivesymptoms(115,117,118).lackedofspeciÞcevidenceforthetreat-mentofacutemanicmixedepisodes.Nodierenceintreatmentecacybetweenlithiumandplacebowasfoundinaretrospectiveanalysis(105)ofarandomized,double-blindstudyondepressivemania(104).Lithiumhasalsobeenstudiedasanadd-ontreatmentofdierentSGAvs.placebo,buttherewasnoplacebocomparisonforthelithiumtreatment(55,56,67).Electroconvulsivetherapy(ECT)wasconsid-eredasasecond-linetreatment(BAPIV,RANZCPIII,WFSBP4)forbothdepressiveandmanicsymptomsofamanicmixedepisode.TheevidenceforECTwasbasedonacaseseriessug-gestthatECTiseectiveinthetreatmentofacutemixedepisodes(119121),onaretrospectivestudyon20manic-depressivemixedpatients(122)andotherobservationalstudies(123125).EventhoughtherewasnoRCTevaluatingtheecacyofECTrelativetoothertreatmentsinmixedaectivestates,ECThasbeenfoundtohaverea-sonableevidenceforitssafeandeectiveuseinmanicmixedpatients,particularlyinthosepatientsrefractorytopharmacotherapy.Finally,thetreatmentsthattheguidelinesadvisedtoavoidwereADmonotherapy,lithiuminmonotherapy(CINP5),antipsychoticsinmonotherapy,particularlyasenapineformanicsymptoms(evidencefromposthocanalysisisnega-tiveforasenapinemonotherapytobeeectiveagainstacutemanicsymptoms,WFSBPcategoryE,CINP5),paliperidonefordepressivesymptoms(WFSBPcategoryE,CINP5),quetiapineforbothmanicanddepressivesymptoms(WFSBPcategoryE,CINP5)andcombinationtreatmentofFGA(haloperidol,WFSBPcategoryE,CINP5),SGA(risperidone,WFSBPcategoryE,CINP5;paliperidone,WFSBPcategoryE),orothertreat-ment,thatis,celecoxib(CINP5).Depressionwithmixedfeaturesordepressivemixedepisodes.Eventhoughdepressionwithmixedfeaturesordepressivemixedepisodesisalreadywell-knownconditions,theyarerelativelynewdiagnosticentitiesandonlyrecentlyresearchontheirspeciÞctreatmenthasbeenconductedandrecommendationguidelineshavebeendeveloped.TherearecurrentlynopsychotropicagentsapprovedbyFDAandEMAforthetreatmentofdepressionwithmixedfeatures.NoMSisactuallyapprovedforuseindepressionofanykindexceptlamotrigine(43).Ingeneral,ADtreatmentinmonotherapyshouldbeavoided(39,43).SGAsaretheonlypsychotropicagentsthathavebeenspeciÞcallytestedforthetreatmentofdepres-sionwithmixedfeatures,butnotallofthemhavedemonstratedecacyinbipolardepression.Asaconsequence,cautionisneededwhenextrapolatingrecommendationsfromstudiesinbipolardepres-sionfordepressionwithmixedfeatures(unipolarorbipolar).inmonotherapyforacutedepressivemixedepisodewasratedasaÞrst-linetreatmentintheStahletal.guidelines(1)andbytheWFSBPincombinationwithtreatmentasusual(3)butasasecond-linetreatmentaccordingtotheCINP(4).Theevidencefortheserecommendationswasbasedona6-week,randomized,placebo-con-trolledtrialonpatientssueringfromBDIIorMDDduringaMDE(126).ZiprasidonewasaddedtotheTAUandcomparedtoplacebo.MixedBDIIandMDDpatientsonziprasidonepresentedhigherresponseandremissionrates,withmorebeneÞtinBDIIthaninMDD,andreduct

ionindepressivesymptomsbutnotinmanicones.Aposthocanalysisofthisstudywascon-ductedtoassessotherpredictorsofresponse,butnosigniÞcanteectwasfound(126).wasratedasaÞrst-linetreatmentbothinmonotherapy(RANZCPI,Stahletal.guidelines2)andincombinationwithMS(CINP2,RANZCPIIwithvalproate,Stahletal.guideli-nes2)orAD(RANZCPII,Stahletal.guidelines2Þrst-linewith”uoxetine).Olanzapinemonother-apy(WFSBP4,CINP3)orthecombinationolan-”uoxetine(CINP4,CANMAT/ISBD2)wasratedasasecond-linetreatmentaccordingtoWFSBP,theCINP,andtheCANMAT/ISBD.Theevidencewascon”ictingandwasbasedonaposthocanalysis(127)ofa8-weekRCTonBD-IMixedstatesandfeaturestreatmentreview patientsduringadepressiveepisodetreatedwithplacebo,olanzapine,orOFC(128).Comparedtoplacebo,botholanzapineandOFCwereeca-cioustreatmentsofbipolardepressionwithmixedfeatures,withOFCbeingthemostecacioustreatment.Apooledanalysis(52)ofthisstudy,togetherwithasecondRCTonBDIpatientswithdepression(129),wasconducted.OlanzapinewassigniÞcantlybetterthanplaceboinreducingdepressivesymptoms,irrespectivelyofthepresenceofconcurrentmanicsymptoms.wasconsideredaÞrst-linetreatmentinmonotherapyorincombinationbyStahlandcolleaguesandbytheCANMAT/ISBD(1),andasasecond-linetreatmentinmonotherapyaccordingtotheWFSBP(4).Lurasidonewasevaluatedinthetreatmentofbipolarmixeddepressionwithaplacebo-controlledmonotherapyRCT(130),apla-cebo-controlledcombinationRCT(131),andasecondcontrolledcombinationtreatmentRCTenrollingMDDpatientswithmixedfeaturesinwhichlurasidonedidnotseparatefromplacebo(132).AposthocanalysisofthemonotherapyRCTwasconductedonpatientswithmixedmanicfeatures(133),andtreatmentwithlurasidonewasassociatedwithsigniÞcantlygreaterreductionsinMADRSscoreswithpossiblecapabilitiesoflurasi-donetopreventtreatmentemergentaectiveswitch(TEAS).Lurasidonewastheonlycom-poundtohavebeeninvestigatedforthetreatmentofMDEwithMFSinthecontextofMDD.Aran-domized,double-blind,placebo-controlledstudy(134)andthreeposthocanalysesofthesameRCThavebeenconductedspeciÞcallyinMDDpatientswithmixedfeatures.TheÞrstposthoc(135)evaluatedtheecacyoflurasidoneintreat-ingMDDwithmixedfeaturesincludingirritabil-ity,withsigniÞcantimprovementatweek6ofMADRSscoreinbothpatientswithandwithoutirritabilityandinspeciÞcYMRSitems(irritabilityanddisruptiveaggressiveness).Thesecondanalysis(136)evaluatedtheecacyoflurasi-doneintreatingpatientswithMDDwithmixedfeaturesandmildandmoderate-to-severelevelsofanxiety,withsigniÞcantchangesin6weeksinMADRStotalscoreforpatientswithbothmildormoderate-to-severeanxietyandchangesinHAMAtotalscore.Thethirdposthocanalysis(137)foundlurasidonetobeeectiveintreatingpost-menopausalMDDpatientswithmixedfeatures.Eventhoughquetiapine(evenintheextended-releaseformulation),asenapine,aripiprazole,andcariprazinewereconsideredaÞrst-linetreatmentaccordingtotheRANZCP(quetiapine)andtotheStahlandcolleaguesguidelines(1)inmonother-apyandincombinationwithanAD(RANXCPIIforquetiapine)oraMS(Stahlandcolleaguesguidelines),andasecond-linetreatmentaccordingtotheCINP(aripiprazole,asenapineCINP3)andtotheCANMAT/ISBD(3),theWFSBPdidnotÞndanysuitablestudyonquetiapine,asenapine,aripiprazole,andcariprazineinacutedepressivemixedepisodestoratetheevidence.TheRANZCPandtheStahlandcolleaguesguidelinesproposedMS,particularly,aloneorincombination,aspossibleÞrst-linetreatmentforacutedepressivemixedstates.wasratedasasec-ond-linetreatmentbytheCINP(3),bytheStahlandcolleaguesguidelines,andbytheWFSBP(4,monotherapyfordepressivesymptoms).Nonethe-less,theWFSBPdidnotÞndanysuitablestudytoratetheevidenceforlithium,lamotrigine,andval-proate.Asforcarbamazepine,noRCTexistsonthetreatmentforacutedepressivemixedstatesbutacaseseries(138)ofcarbamazepinemonotherapyinbipolardepression(9)reportedimprove-mentofHamiltonDepressionRatingScaleHAMD)depressivesymptoms.wasrecommendedasasecond-linetreat-mentincombinationwithMS(WFSBP4,Stahlandcolleaguesguidelines3)onthebasisofsub-analysesofobservationalstudies.TheAgitated-IrritableMixed-DepressiongroupinthestudybyMeddaandcolleagues(121)wasfoundtohavethegreatestimprovementfromECT(139).Otherrec

ommendedsecond-linetreatmentsbyStahlandcolleagueswerethecombinationofMSorSGAwithbupropion,SSRI,orMAOI.inmonother-apy(WFSBP,Stahlandcolleaguesguidelines),(Sthalandcolleaguesguidelines),risperidone,haloperidol,incombina-tionwithMS(CINP),carbamazepine+olanzap-ine,orrisperidone(Stahlandcolleaguesguidelines)arenotrecommendedtreatmentsinacutedepressivemixedstates.Maintenancetreatment.MSandSGAwereratedasecacioustreatmentinthelong-termmanage-mentofmixedstates.werethetreatmentsthatwereconsideredaseectiveinthepreventionofanewmixedepisodeafteranacutemanicordepressedindexepisode,withscantandcon”ictingevidence.Olanzapineandlithiumwereratedasasecond-linetreatmentinpreventingmixedrecurrenceaccordingtotheWFSBP(5)whiletheBAPratedlithiumasaÞrst-linetreat-mentagainstmixedrelapse.(WFSBP5,BAPI)and(WFSBP3)weresigniÞcantlyassociatedwithareducedrateofadmissionsVerdolinietal. becauseofamixedepisodeinabigobservationalSwedishregistrystudy(140).Inare-analysis(141)ofanhead-toheadcomparisonRCTolanzapinevs.lithium(142),olanzapinehadasigniÞcantlylowerriskofsymptomaticmixedepisoderelapse/recurrencethanlithium.ValproatewastheonlycompoundratedasaÞrst-linetreatmentinthepre-ventionofanewmixedepisodeonthebasisoftheresultsofameta-analysis(143)thatincludesa20-monthmaintenanceRCTcomparingvalproateandlithiumwithoutnoplacebo-arm(144)showingnostatisticaldierencebetweenvalproateandlithiuminpreventingamixedepisode.Thestudywasdiculttoratebecauseitwasevaluatedinthemeta-analysisandlithiummightbenottheidealstandardcomparator.Negativeevidence(E)wasreportedforaripiprazole(afteramanicindexepisode),carbamazepine,lamotrigine,queti-apineinpreventinganewmixedepisode.Inthepreventionofepisodesofanypolarityafteramixedindexepisode,inmonother-apyorincombinationwasconsideredaÞrst-linetreatment(BAPI,WFSBP3)onthebasisoftheresultsofretrospectivestudies(145148),mainte-nanceRCT(149),andsubanalysisofmaintenanceRCT(150).Nonetheless,valproatewasfoundtobeevenmoreeectivethanlithium(RANZCP)inthepreventionofnewaectiveepisodesinaanalysis(151)ondysphoricmania(123)ofa12-monthmaintenancestudycomparingval-proate,lithium,andplacebo(152).Theseresultswereatoddswiththoseofanobservationalcohortstudy(146)withlinkageofnationwideregistersinwhichtheoverallrateofhospitaladmissionswassigniÞcantlyincreasedforvalproatecomparedwithlithiuminpatientswithamixedindexepisode.Becauseofthiscon”ictingevidence,valproatewasratedasE(negativeevidence)accordingtotheWFSBPandconsequentlynotrecommendedinthepreventionofepisodesofanypolarity.waspoorlystudiedasamaintenancetreatmentforpatientswithamixedstates,andtheavailableevidencewasdiculttoratebecauseoflimitationsinthestudydesign.Infact,theecacyofcarbamazepineextended-releaseasmaintenancetreatmentwasevaluatedinbipolarpatientsduringamanicormixedepisodebutthedataofthesepa-rateanalysisforthemixedsubgroupwereonlyreportedfordepressivesymptoms.CarbamazepinetreatmentmaintainedthesigniÞcantdecreaseofdepressivesymptoms,buttheevidenceisnotcon-Þrmativeintheabsenceofreportednumbersforrelapses(153).inmonotherapywasrecommendedasaÞrst-linetreatment(CINP2,WFSBP3)inthepreventionofanytypeofaectiveepisodesafteranacutemixedepisodeonthebasisofaRCTformaintenancetreatmentcomparingolanzapinevs.placebo(154)anditsposthocanalysis(155).Infact,olanzapine-treatedpatientsshowedsigniÞ-cantlylowerratesofsymptomaticrelapseofanykind.NodeÞnitedataareavailableforthecombi-nationwithlithiumorvalproateastheonlyRCTconductedonolanzapineMSdidnotreportsep-arateresultsformixedpatients(156).Eventhoughtheevidencewasquitegood,thesecond-linerec-ommendationbytheWFSBPwasmainlybecauseofprofoundconcernsaboutweightgainandlong-termmetaboliceectsofolanzapineinthelong-wasconsideredasaÞrst-linetreat-mentbothinmonotherapy(WFSBP3,formanicandforanytypeofepisodeprevention;CAN-MAT/ISBD1)andincombinationwithlithiumorvalproate(WFSBP2,CANMAT/ISBD1,formanic,depressive,andanytypeofepisodepreven-tion).Theevidencefortheserecommendationswasbasedonalargerelapseandrecurrencepre-ventionRCT(147)withawidemixedpatientssub-group(223),ontwoidenticallydesignedRCTcom

paringquetiapinevs.placebolithiumorval-proate(157,158),andaposthocanalysisofthemixedpatientsincludedinthetwopreviousRCTthatconÞrmedtheecacyofquetiapineinthelong-termtreatment(159).Asfor,itwasasecond-linetreatmentformanicrelapseinmonotherapy(WFSBP4)onthebasisofamonotherapy(68)andacombinationRCT(160).wasrecommendedasaÞrst-linestrategyinthepreventionofepisodesofanypolar-ityincombinationtreatmentwithMS(CINP2).TheWFSBPtask-forceratedaripiprazoleasasec-ond-linestrategyfordepressiverecurrenceincom-binationwithlamotrigine(WFSBP4)butreportednegativeevidence(E)foraripiprazole(lithiumorvalproate)inthepreventionofanyepi-sode.Theevidencefortheserecommendationsisbasedonaposthocanalysis(161)ofa52-weekmaintenancecombinationstudyofaripiprazoleMSvs.placebo(162)thatfoundnosigniÞcantadvantageofaripiprazoleforthegroupofmixedpatientsfortimetoanyrelapse,asmallmainte-nanceRCT,withnoseparateoutcomesreportedformixedpatients(163)andaposthocanalysisofa52-weekRCTtestinglamotriginearipiprazolevs.lamotrigineplacebo(164)show-ingthattimetorelapsetoadepressiveepisodewassigniÞcantlylongerwiththearipiprazolecombina-tioncomparedwiththeplacebo.Dataonthemaintenancetreatmentofaripiprazoleinmonotherapyarenotavailable.Mixedstatesandfeaturestreatmentreview wasrecommendedasasecond-linetreatment(WFSBP4)incombination/augmenta-tiontherapyafteramixedindexepisodeinpre-ventingepisodesofanypolarityonthebasisoftwoopen-labelstudiesinwhichrisperidoneaddedtolithiumorvalproatesuppliedevidenceforacuteecacymaintainedlong-term(6months)(165)andpresentedsigniÞcantimprovementofbothmanicanddepressivesymptomsover24weeksEventhoughlittleisknownabouttheimpactofonthelong-termoutcomeofbipolarpatients,theWFSBPtask-forcerecommendsECTasasecond-linemaintenancetreatmentincombi-nationwithaMS(WFSBP4)onthebasisofacaseseries(167),aprospectivenaturalisticstudy(168)andanaturalisticstudyonrapid-cyclingpatientsunresponsivetoprophylacticMS(169).Asfor,itwasnotpossibletoratetheevidenceforthelong-termtreatmentbecauseinthethreestudiesaimedatinvestigatingtheecacyoflurasidonevs.placeboincludingmixedpatients172),noseparateoutcomehasbeenreportedforthisgroup.Arecentposthocanalysisevaluat-ingremissionandrecoveryassociatedwithlurasi-doneinthetreatmentofMDDwithmixedfeatures(173)reportedpatientstreatedwithlurasi-donesigniÞcantlyachievedrecoverycomparedtoplaceboafter6weeksoftreatment,butthisstudywasnotincludedintheconsideredguidelines.Theevidenceforlong-termtreatmentofADwasscant,andTheInternationalSocietyforBipo-larDisorders(ISBD)task-forcediscouragedtheuseofADuseinBDbecauseofsafetyreasons(174).Stahlandcolleaguesunderlinedthatasmallminorityofpatientspresentingadepressiveepi-sodewithmixedfeaturescouldimprovewithalong-termtreatmentthatincludesanAD,butonlyasanadjuncttoMS.ComparisonofthedifferentguidelinesAsageneralrule,alltheguidelinesincludedwerecreatedwithoutanyÞnancialsupportfromphar-maceuticalcompaniesandexpertsofthetask-forcewereselectedaccordingtotheirexpertise.Guideli-neshavebeendevelopedbymultidisciplinaryteamsinvolvingexpertsfromdierentcountriestofacilitatetheirapplicabilityaroundtheworld.TheBAPguidelineswereattheirthirdrevisionandtheCANMATguidelinesattheir4thupdate,whiletheotherguidelinesincludedinthiscriticalreviewwereattheirÞrstedition.TheBAPguidelines,theRANZCPMoodDisordersCPG,theCINP-BD-2017,andtheCANMATguidelineswereprimarilyaimedatprovidingrecommendationsforthetreatmentofBDormooddisordersingeneralwhiletheWFSBPguidelinesandtheStahlandcolleaguesguidelinesfocusedonmixedstatesormixedfeatures.TheWFSBPhadtheirprimaryscopeontheacuteandlong-termtreatmentofmanicordepressivemixedepisodesinBDIdisorderascategorizedinDSM-IVandDSM-5whiletheStahlandcolleaguesguidelinesweredevelopedtohelpintherecogni-tionandmanagementofaMDEwithmixedfea-turesinthecontextofBDorMDDinreferencetoDSM-5criteria.StahlandcolleaguesguidelinesdidnotreportseparatedtreatmentstrategiesforBDandMDDwithMFSbutsimplyreferredtodepressionwithmixedfeaturesormixeddepres-Dierentaimscorrespondedtodierentmeth-ods.Asaconsequence,theguidelinesdieredintheirmethodology.Asfor

theliteraturesearchmethodology,thearticlesincludedineachguidelinevariedaccordingtothespeciÞcpurposeofthedierenttask-forces.ThemethodologyoftheBAPguidelinesdidnotallowforasystematicreviewofallpossibledatafromprimarysourcesandpublicationsidentiÞeduptoDecember2015.Similarly,theStahlandcol-leaguesguidelinesaswellastheCANMAT/ISBDupdate2018didnotprovideatimelimitationorinformationabouttheliteraturesearch.TheRANZCPtask-forcedidnotreportthetimelimi-tationoftheliteraturesearchbutassessedthatthesamesearchwasrepeatedregularlybetweenApril2013andOctober2015.TheCINPguidelineshavebeendevelopedfollowingthePRISMAmethod,andasystematicsearchwasconducteduptoMarch25,2016.Finally,theWFSBPtask-forceconductedtheoriginalsearchonMay29,2013,anditwasupdatedonMarch12,2017.ThemethodologyofthedeÞnitionofcategoryofevidenceandtherecommendationgradesvariedacrosstheincludedguidelines.TheBAPguidelineswerethemostelaboratedandusedtheGRADEapproachtojustifythequalitystandardofrecom-mendations,includingbothRCTandobserva-tionalstudiestoprovidemoreobjectiveandhighlyclinicallyrelevantrecommendations.Onthecon-trary,theprocessusedtogatherandsynthesizetheevidenceandthemethodstoformulatetherecom-mendationsintheStahlandcolleaguesguidelines,whichweremoreclinical-expertiseorientedthanevidence-baseoriented,wasnotwellstated,ascon-Þrmedbythelow-qualityscoreoftheAGREEIIdomain3.TheÞrstmaindistinctionacrossguidelinescamefromthedierentweightgiventoposthocses,astheyplayaprominentroleinstudiesVerdolinietal. includingmixedpatients.AccordingtotheWFSBP,whenaposthocanalysishasbeenaprioriintheanalysesplanandissu-cientlypowered,aCEBcouldbeconsidered.Onthecontrary,theCINPcollegeratedposthocysesaslevel3oftheecacygradingwithdiscrep-anciesintherecommendationgradesbetweentheguidelines.NospeciÞcgradingforposthocseswasprovidedbytheotherguidelines.Inaddition,boththeBAPandtheWFSBPtaskforcesdecidedtoacceptregistryobservationalstudiesintheirevidencecategoriestotakeincon-siderationthevaluableinformationaboutthereal-worldeectivenessandacceptanceoftreat-mentmodalitiesthatthesestudiescouldprovide,withdierentgradesofecacyonthebasisofthequalityofthestudies.TheCANMAT/ISBDguide-linesincludedhealthsystemadministrativedatabutratedthemasCE3.Anotherpointistheimportancegiventometa-analyses.Alltheguidelines,WFSBPandCINPguidelinesexcluded,deÞnethepresenceofpositiveresultsfrommeta-analysesasfullevidencefortheecacyofadeterminedcompound(notclearintheStahlandcolleaguesguidelines).Particularly,theCANMAT/ISBDtaskforcedierentiatedtheevidencefrommeta-analysisonthebasisofthenarroworwideconÞdenceintervals(CE1or2respectively).Onthecontrary,theWFSBPtask-forcedidnotusetheresultsofmeta-analysesasevidenceofthesameleveloftheresultsfromsingleRCTfulÞllinginclusioncriteria.Meta-analyseswereonlyusedinthecaseofexistingnegativestud-iestogradetheevidenceinthecaseofstudiesshowingnon-superioritytoplaceboorinferioritytocomparatortreatment.ThemembersoftheCINPcollegeincludedmeta-analysesintheevi-dencetheygradedbutconsideredthemasasecondleveloftheecacygrading,prioritizinggoodresearch-basedevidencesupportedbyatleast2placebo-controlledstudiesofsucientmagnitudeandgoodquality.ClinicalmessagesAccordingtotheguidelinesincludedinthiscriticalreview,theacutetreatmentofbothdepressiveandmanic/hypomanicmixedepisodesisbasedonSGA.LithiumandvalproateaswellasSGAwerefoundtobeecaciousinthepreventionofnewaectiveepisodes.Thechoicebetweenthedierentcompoundsshouldbemadeonthebasisofclinicalissuesthatarisefromtheserecommendations.Particularly,recommendationgrades(RG)foreachcompoundhavebeengenerallyderivedfromsafetyandtolerabilityaspectsintegratedwithCE,withfewexceptions.Indeed,theBAP,theMoodCPG,andtheSthalandcolleaguesguidelinesdidnotreportagradingforsafetyandtolerability.SGAwerethepsychotropicagentsthathavebeengenerallyconsideredasÞrst-linechoiceinthetreatmentofacutemania/hypomaniaordepres-sionwithmixedfeaturesinalltheguidelines.ThecompoundsidentiÞedasSGAdieredwidelybetweenthem,mainlyintermsofsafetyandlong-termtolerability(175),particularlyinthemainte-nancetre

atment,resultinginadowngradingoftheRG,especiallywhenmakingadistinctionbetweenRG1and2(i.e.,olanzapine).Anotherimportantclinicalaspectinguidingthechoiceofmaintenancetherapyshouldbethepolar-ityindexofthedierentcompounds(176).SGAssuchasrisperidone,aripiprazole,ziprasidone,olanzapine,quetiapine,andothercompoundssuchaslithiumhaveapolarityindexsuperiorto1whichmeansthattheyarebetterpreventingmaniathandepression.Onlylamotrigineandlurasidonehaveapolarityindexunder1(andare,thus,bettersuitedforpatientswithdepressivepredominantpolarity)(177).Thesegeneralconsiderationscangetevenmorecomplicatedwhenitcomestomixedstatesforthepresenceofintertwinedoppositesymptomsthatmaychangetheantimanicordepressiveprophylacticecacy.Pharmacotherapyofmixedstatesischallengingbecauseantipsy-choticsusedtotreatmanicsymptoms,andADcouldpotentiallydeterioratesymptomsoftheoppositepolarity(13).Accordingtothepolarityindex(177),lamotrigineandlurasidonemighthaveadepressivepreventiveecacyinBDmaintenancetreatment,butcurrently,theevidenceisstilllack-ingforthelong-termtreatmentofmixedepisodes.Onlylithium,olanzapine,andquetiapineinmonotherapyhadrobustevidenceforthepreven-tionofnewdepressiveepisodesintheguidelinesincludedinthiscriticalreview.Asaconsequence,thepreventionofdepressiverecurrenceisstillachallengingpoint,mainlybecauseofthelackofevidenceforthepreventingeectofSGA,MS,andantiepilepticcompounds.ThescarcityofresearchedtreatmentoptionsisfrequentlyassociatedwithaclinicalmanagementthatoftenreliesonAD(178).TheInternationalSocietyforBipolarDisorders(ISBD)Task-forceReportonADuseinBipolarDisorders(174)rec-ommendsavoidingADuseinBDpatientswithahistoryofpastmania,hypomania,ormixedepi-sodesemergingduringpreviousADtreatmentandthatshouldbeavoidedinpatientswithhighmoodinstabilityorwithahistoryofrapidcycling.Despitethis,thereisstillawideuseofADinthereal-worldclinicalpsychiatry(179181)despitetheMixedstatesandfeaturestreatmentreview weakevidencefortheecacyandsafetyofADinBD.TheEMBLEMstudyreportedthatmoreADmaintenanceusewasseeninpatientswithmixedepisodes(179).ThetwomainconsequencesintheuseofADinpatientswithmixedfeaturesaretheriskofswitchinginmaniaandtheriskofsuicide.ArecentposthocanalysisoftheBRIDGE-II-MIXstudy(182)underlinedthatAD-inducedhypoma-nia/maniapatientswithMDDreportedhigherratesoftreatmentresistance,moodlability,andirritabilityfollowingtreatmentwithADandweremainlyrepresentedinthegroupsofdepressedpatientswithmixedfeaturesandamongBDpatients.Asfortheriskofsuicide,severalstudiesfoundanassociationoflifetimemixedepisodes,higherratesofADuse,andincreasedriskofsui-cidebehaviors(183185).ItisforthisreasonthattheISBDtask-forcerecommendedthatADinBDpatientsshouldbeprescribedonlyasanadjuncttomood-stabilizingmedications(174).AsunderlinedbyStahlandcolleagues,ADmayprotectfromdepressiverecurrencesinasmallminorityofpatientswithmixedfeatures,bothinbipolarandinunipolarpatients(43,186),especiallyifpre-scribedincombinationwithantimanicagents.TheideaisthatMDEwithmixedfeaturesshouldbevieweddierentlyfromunipolarMDEwithoutmixedfeaturesintermsofnaturalhistory,clinicaloutcome,andtreatment(5).Mixedfea-turesinMDDhavebeenseentoberelatedtohighrecurrence(187)andotherdetrimentalclinicalcor-relates,suchashigherriskofsuicide(188),obesity(189),andborderlinepersonalitydisorderscomor-bidity(190)inrecentBRDGE-II-Mixposthocanalyses.Furthermore,nearlyaquarterofpatientssueringfromMDDmayconverttoBD(191).AccordingtotheÞndingsoftworecentmeta-ana-lyses(191,192),thetransitionfromMDDtoBDwaspredictedbyclinicalfeaturessuchasfamilyhistoryofBD,earlierageofonsetofdepression,thepresenceofpsychoticsymptoms(191,192),thenumberofdepressiveepisodes,theresistancetoAD,theseverityofdepression,theprevalenceofchronicdepression(192)and,interestingly,sub-thresholdmanicsymptomsduringaMDE(191).Hence,theMFSmayserveaclinicallyrele-vantroleasawarningsignforbipolarity,inspiteofitslimitations.ThefactthatcertainantipsychoticsorMSshouldbegivenasÞrst-lineintheacuteandlong-termtreatmentofmixedMDEratherthanADmonotherapyshouldleadtoaparadigmshiftinthesafeandcomforta

bleuseofAD,preferringthemoredangerousanduncomfortablecom-poundssuchasSGAandMS(193).Indeed,psychiatristsarecalledtochoosebetweenover-diagnosisofMDEwithMFSbettertreatedwithSGAormissingthediagnosisofmixedsymptomsandtreatingthepatientwithADwithconsequenttreatmentresistanceofharmfulside-eects(sui-cide,switchesintohypo/mania)(194).Inlinewiththisaspect,themostimportantvirtueoftheDSM-5MFScouldbethehighersensitivitythantheDSM-IV-TRmixedepisodesclassiÞcationintheidentiÞcationoftheorthogonalaspectsofsui-cidality(i.e.,suicidalideation,suicideattempts)(2).AsmixeddepressiveepisodesarethreetimesmorecommoninBDIIcomparedtoMDD,thepossibilitytoapplytheMFSeventoBDIIwouldallowamoreaccurateidentiÞcationofsuicidaltendencies(2,9).Finally,thereisgrowingevidencesuggestingthatmixedsymptomscommonlycontributetopoortreatmentresponsewithimplicationsofpotentiallylesssatisfactoryresponsetotreatment197)(LevelIVBAP).Clozapineincombi-nationtreatmentwithMSwasfoundtobesupe-riortoTAUintreatment-resistantpatientsduringamixedmanicepisode.EventhoughECTisoftenaneglectedtreatmentoptioncarryingtheburdenofunfavorablemediaportrayalandwronggeneralbeliefsandthusfrequentlyusedasalast-resort-treatmentforseverebipolarpatients(178),ithasbeenfoundtohavereasonableevi-denceforitssafeandeectiveuseinmanicmixedpatients,particularlyinthosepatientsrefractorytopharmacotherapy.MethodologicallimitationsThiscriticalreviewhaslimitations,mainlydepend-ingonthemethodologicalissuesoftheincludedTheguidelinesincludedinthiscriticaloverviewreportedonthetreatmentofmanic/hypomanicanddepressiveepisodeswithmixedfeaturesormixedstates,usingdierentdiagnosticcriteria(DSM-IVorDSM-5)todeÞnemixedsymptoms.Alltheguidelinesincludedinthiscriticalreviewlackofstrengthintheapplicabilitydomain,whichevaluatetheresourceimplicationsofapplyingtheguideline,thebarriers,andfacilitatorstoimple-mentationandthestrategiestoimproveuptake(34).Theguidelinesincluded,exceptfromtheBAPguidelines,didnotreportaboutmonitoringorauditingcriteria;consequently,itwillbeimpossi-bletorateimprovedoutcomesforpatientstreatedinaccordancewiththeseguidelines.Ideally,guide-linesshouldevaluatetheroleofspeciÞcpharmaco-logicalinterventionsinthetreatmentofmixedstatesconsideringecacyandreal-worldeective-ness(31)buttheguidelinesincludeddidnotreportVerdolinietal. aboutfacilitatorsandbarrierstotheirapplicationorontheresourceimplicationsoftheapplicabilityoftheirrecommendations.Anothercommonmethodological”awofthestudiesincludedintheguidelinesconsideringtreat-mentformixedstateswasthattheresponseofmixedpatientstopharmacologicalagentshadbeenextrapolatedfromposthocorpooledanalysesofRCTthathaveenrolledbothpureandmixedmanicpatients,assumingacomparableresponsetotreatmentforbothsubgroupsofpatients(22).GiventheseveralcriticismsarisentowardthedierentclassiÞcationsofmixedstatesandmixedfeaturesinthedierenteditionsoftheDSM,manyresearcherstriedtoprovidealternativedeÞnitionsandtoadoptdierentcriteriafordiagnosismixedpresentations(198201).Asthereisnotaconsen-susregardingthedeÞnitionofmixedstatesandbecauseofthemajorconcernsabouttheDSM-5MFS,itisnotsurprisingthatthereisapaucityofevidenceexaminingtreatmentoutcomesandmixedfeatureshavebeenassessedposthocandwithacross-sectionaldesigninthemostrecentliterature(13).Indeed,onlyfewoftheRCTsincludedintheguidelinesconsideredtheDSM-5MFSasthepri-maryoutcomeoftreatmentsforbipolarhypo-manic,manic,anddepressiveepisodes.Anotherfurthermajor”awoftheliteratureisthatmixeddepressivepatientsarenotusuallyreportedindepressionRCT(24).Furthermore,theevidenceaboutthetreatmentofMDDwithMFSisstillscantandlimitedtolurasidone(134173).Accordingly,theguidelinesincludedinthissystematicreviewdidnotdierentiatethetreat-mentforMDEwithMFSinthecontextofBDorMDD(43).Oneofthemostimportantlimitationsofguideli-nesistheirexcessiverelianceonevidence-baseddataresultingfromRCT,whichbringimportantlimitsintheirdesignsuchaspoorgeneralizabilityoftheresultsandthesponsorbias.Interestingly,onlytheBAPguidelinesconsideredobservationalstudiesandindependenttrials.Thesestudieshavemethodologica

llimitationsandlowerinternalvaliditythanRCTs,buttheyaremuchmoregener-alizableandmayhavelesssponsorbias(36,202).Indeed,arecentsystematicreviewassessingtheeectivenessofmaintenancetreatmentoflithiumvs.othermoodstabilizershighlightedthatRCTsareaectedbymethodologicallimitations,speciÞ-callyinthecaseofcomparativemaintenancetrialsFewmethodologicallimitationsofthesystem-aticreviewitselfwereworthytobementioned.Intheattempttobeasrigorousaspossible,theauthorsdecidedtoconsideraseligibleonlyinternationalguidelinesresultinginonlysixguide-linesmeetingalltheinclusioncriteria,withtheexclusionofnationalguidelines.Despitethis,thescientiÞcvaluederivedbytheinternationalteamswithexpertsfromdierentcountriesoftheincludedguidelinescouldinsuretheirapplicabilityaroundtheworldandnotonlyonanationalbasis.Finally,asthequalitymethodologyoftheincludedguidelineswasassessedwiththeAGREEIItool,theauthorsofthissystematicreviewcouldnotcompletelyexcludethattheÞndingsmaybein”u-encedbytheinterpretationandrankingoftheevi-dencebythetworeviewers(NVandDHM).Nonetheless,thetworeviewerssuccessfullycom-pletedthetrainingmodulesoftheAGREEIItoolandundertookindependentappraisalsforeachoftheincludedguidelines,warrantingtherigorofthemethodologyofthissystematiccriticalreviewandthereliabilityofitsÞndings.FutureperspectivesFromadiagnosticpointofview,adimensionalapproachdeÞningthemostparsimoniousclinicalmodelaimedatunderstandingthespeciÞcityoftherelationshipofmixedfeatureswithinthecontextofbipolarvs.unipolardisordersisneeded.Theclini-calpresentationscouldbebestcharacterizedalonganumberofdomains,inwhichcognitionandenergyplaycriticalrolesinmixedpresentationsintermsofattention,memory,motivation,drive,andbehavioralactivitythatshouldbebetterunder-stoodandrated.Moodcouldalsobeassessed,withafocusonspeciÞcsymptomsratherthansymptomclustersordiagnosticsyndromes,withadierentiationbetweenspontaneousmixedstatesandthoseinducedbytreatment(13).ClinicalmixedpresentationsshouldalsobedierentiatedbyothercourseandcomorbidspeciÞers,suchasanxiousdistressoratypicalsymptoms.Inaddition,cliniciansshouldassesstheclinicalaspectsofmixedpresentationsnotonlyevaluatingthesingleaectivemixedepisodebutalsotryingtounder-standthelongitudinalcourseofaectivedisorderspresentingwithmixedcomponents.Abetterunderstandingoftheneurobiologyofmixedstateswillbenecessarytodevelopmoreeectivetreatments(203).Indeed,itisnotcom-pletelyclearwhicharetheclinicalcharacteristicsofpatientsexperiencingmixedfeaturesthatcanÞrmlypredicttreatmentresponseorside-eects.Geneticandneurobiologicalresearchcouldhelpidentifyingnewcompounds,proÞlesofresponse,andsafety/tolerabilityconcernsinmixedpatientsintheper-spectiveofapersonalizedpharmacologicaltreat-mentforthedierentsubtypesofmixedstates.Mixedstatesandfeaturestreatmentreview Futureresearchshouldtrytoovercomethelimi-tationsofthecurrentinadequateamountofdataonmixedstatestreatment(25).Oneofthemostimportantproblemsinrecommendingtreatmentsinmixedstatesisthelackofevidenceformanycompoundsthatcouldbepossiblyusedintheacuteandlong-termtreatmentofmixedstates(i.e.,RCTonlong-termtreatmentwithasenapine,lurasidone,orlamotrigineinmonotherapyformixedpatients).Clinicalwell-designedadequatelypowereddouble-blindplacebo-controlledstudiesassessingtheecacy,safety,andtolerabilityofpsychotropicagentsinmania,hypomania,ordepressionwithmixedfeaturesareneeded.Com-poundsthatarealreadyknowntobeeective(i.e.,olanzapine)aswellascontroversialoptions(i.e.,carbamazepine,lamotrigine)deserveabetterunderstanding.Inaddition,largeobservationalstudiesareneededbecauseofthepossibilitytoidentifyreal-worldclinicalvariablesassociatedwiththetreatmentofmixedstates.AspeciÞcfocusshouldbethelong-termtreat-mentasitrepresentsanoftenignoredbutfunda-mentaltopicinthetreatmentofthemixedpresentations.Particularly,manytreatmentoptions,includingoldwell-knownmedicationssuchascarbamazepine,lamotrigine,orevenrela-tivelynewcompoundssuchasasenapine,lurasi-done,andpaliperidone,havenotbeenstudiedindepthinmixedpatientsthelong-term.Aspsychotherapiesandpsychoeducationareim

portantandwelldocumentedtechniquesforimprovingcomplianceandresilienceagainstmoodchangesinthetreatmentofbipolardisorder,theirintegrativeroleandestablishedcomponentoftreatmentshouldbebetterinvestigatedinmixedaectivepresentations.Indeed,psychotherapeutictrialsshowedecacyinbipolardepressivesymp-tomsandinmaintenancetreatment,asadd-ontreatmenttomedicationinbothcases,butnopsy-chotherapyhasyetprovidedanalternativestrat-egyformanagementofpatientsinacutemanicphases(36).Tothebestofourknowledge,nostudyreportedonpsychotherapyinacutemixedpatientssofar.Onlyonestudyhasbeenpublishedonrecurrencepreventionofmixedepisodes,withadjunctivepsychoeducationthatwasfoundtobeeectiveindelayingthetimetoanewmixedepi-sode(204).Inconclusion,treatmentguidelinesareausefultooltoguidethemanagementofacuteandlong-termtreatmentofaectivemixedclinicalpresenta-tionstogetherwithprofessionalknowledgeandclinicaljudgment,intheattempttoorientateclini-calpracticetowardevidencebase.Inmixedstates,despitetheirheterogeneity,allguidelinesagreewithinterruptinganongoingADmonotherapyandaddingmood-stabilizingmedications.Olanza-pinemighthavethebestevidenceforthetreatmentofacutemixedhypo/manicordepressivestatesaswellasmaintenancetreatmentofmixedpresenta-tionsinpreventingnewmixedepisodesoraectiveepisodesofanypolarity.Aripiprazoleandpaliperi-doneinmonotherapyseemedtobeeectivealter-nativesinthetreatmentofacutehypo/manicmixedstateswhilelurasidoneandziprasidone(incombination)revealedaspromisingSGAsubsti-tutesinthetreatmentofacutedepressivemanifes-tationswithouttheadverseeectsloadofolanzapine.Asforthemaintenancetreatment,val-proatewasrecommendedinthepreventionofnewmixedepisodeswhilelithiumaswellascombina-tiontreatmentofquetiapinewasratedaseectiveinpreventingaectiveepisodesofallpolarities.Finally,clozapineandespeciallyECTareoptionstoconsiderintreatment-resistantpresentations.TheseÞndingsshouldbekeptwithcautionastheavailableevidenceisstillscant.Forexample,tosupportthesuperiorityofolanzapine,largecom-parativeRCTsshouldbeconductedassessingitsecacyvs.othercompoundsandnotonlyvs.Theproblemofwhichguidelineisbetterisadif-Þcultone.Theincludedguidelinesshowedhighsci-entiÞcstandardsandgoodmethodologieswithsomedierencesbetweentheguidelinesmentionedinthiscriticalreviewthatcouldorientatetheclini-ciansinthechoiceofwhichguidelinetofollow.Accordingtomethodologicalrobustness,thequal-ityoftheBAPguidelineswasundoubtedlythebest,re”ectedbythehighestAGREEIIoverallassessmentrateamongtheincludedguidelines.Nonetheless,thetreatmentofmixedstatescouldnotbelongerderivedfromthetreatmentofmanicordepressiveepisodesinthecontextofbipolardis-orderbecauseofthenewDSM-5mixedfeaturesspeciÞerwhichisalsoapplicabletounipolardepression.Inthissense,theWFSBPGuidelinesfortheBiologicalTreatmentofBipolarDisorders:AcuteandLong-termTreatmentofMixedstatesinBipolarDisorderrepresentedthemostfocusedguidelinesonthetreatmentofmixedstates,withtheaddedvalueofasimilarlygoodglobalquality.Conversely,theStahlandcolleaguesguidelinesweretheÞrstonetoaddressdepressionwithDSM-5mixedfeatures,althoughconcernwasraisedfortherigorofdevelopmentandtheoverallassess-mentrate.TheCANMAT/ISBDguidelines,Þnally,arethemostrecentandup-to-date.Inclini-calpractice,treatmentguidelinesareasuitableframeworktostartthinkingonthemanagementstrategyforaparticularpatient,butdecisionsneedVerdolinietal. alwaystobeindividualizedinthegrowingcontextofpersonalizedmedicine.TheauthorsthankthesupportoftheSpanishMinistryofEconomyandCompetitivenessintegratedintothePlanNacio-naldeIIandco-ÞnancedbytheISCIII-SubdireccionGen-eraldeEvaluacionandtheFondoEuropeodeDesarrolloRegional(FEDER);theInstitutodeSaludCarlosIIIthatsup-portedthisworkthroughaRšoHortegacontract(CM17/00258)toNV);theCIBERSAM(CentrodeInvestigaciedicaenReddeSaludMental);theSecretariadUniversitatsiRecercadelDepartamentdEconomiaiConeixement(2017SGR1365);andtheCERCAProgramme/GeneralitatdeCatalunya.ThisreportrepresentsindependentresearchpartiallyfundedbytheNationalInstituteforHealthResearch(NIHR)BiomedicalResearchCentreatSouthLon-donandMaud

sleyNHSFoundationTrustandKingsCollegeLondon.TheviewsexpressedarethoseoftheauthorsandnotnecessarilythoseoftheNHS,theNIHR,ortheDepartmentofDeclarationofinterestDr.NormaVerdoliniisfundedbytheSpanishMinistryofEconomyandCompetitiveness,InstitutodeSaludCarlosIIIthroughaRšoHortegacontract(CM17/00258)andreportsnocompetinginterests.Dr.Hidalgohasnocon”ictofinter-esttodeclare.Dr.Murruhasservedasaconsultant,adviser,orspeakerforAdamed,AstraZeneca,Bristol-MyersSquibb,Janssen-Cilag,Lundbeck,Otsuka,andSanoÞ-Aventis.Dr.hasreceivedCME-relatedhonoraria,orconsult-ingfeesfromADAMED,Janssen-CilagandLundbeck.hasreceivedgrants,honoraria,orconsultingfeesfromAstraZeneca,Bristol-MyersSquibb,Janssen-Cilag,Lundbeck,Otsuka,SanoÞ-Aventis,andTakeda.Prof.Younghasthefollowingdisclosures.EmployedbyKingsCollegeLondon.HonoraryconsultantSLaM(NHSUK).Paidlec-turesandadvisoryboardsforallmajorpharmaceuticalcom-panieswithdrugsusedinaectiveandrelateddisorders.Noshareholdingsinpharmaceuticalcompanies.LeadInvestiga-torfortheEmboldenStudy(AZ),theBCINeuroplasticityStudy,andtheAripiprazoleManiaStudy.Investigator-initiatedstudiesfromAZ,Eli-Lilly,Lundbeck,andWyeth.Grantfunding(pastandpresent):NIMH(USA),CIHR(Canada),NARSAD(USA),StanleyMedicalResearchInsti-tute(USA),MRC(UK),WellcomeTrust(UK).theRoyalCollegeofPhysicians(Edin),BMA(UK),UBCVGHFoun-dation(Canada),WEDC(Canada),CCSDepressionResearchFund(Canada),MSFHR(Canada),andNIHRProf.Vietahasreceivedresearchsupportfromorservedasconsultant,adviser,orspeakerforAB-Biotics,Actavis,Allergan,AstraZeneca,Bristol-MyersSquibb,DainipponSumitomoPharma,Ferrer,ForestResearchInsti-tute,GedeonRichter,Glaxo-Smith-Kline,Janssen,Lund-beck,Otsuka,PÞzer,Roche,SanoÞ-Aventis,Servier,Shire,Sunovion,Takeda,Telefonica,theBrainandBehaviourFoundation,theSpanishMinistryofScienceandInnovation(CIBERSAM),theSeventhEuropeanFrameworkPro-gramme(ENBREC),andtheStanleyMedicalResearchDr.Carvalhoistherecipientofaresearchfellow-shipawardfromtheConselhodeDesenvolvimentošÞcoeTecnologico(CNPq;Brazil).Roleofthefunder/sponsorThefundingsourceshadnoroleinthedesignandconductofthestudy;collection,management,analysis,andinterpretationofthedata;preparation,review,orapprovalofthemanu-script;anddecisiontosubmitthemanuscriptforpublication.E.Bipolardisorder.Lancet2016;E.Mixedfeaturesinbipolardisorder.CNSSpectr2017;A.Originanddevelopmentofconceptsofbipolarmixedstates.JAectDisord2001;RS.Treatmentrecommenda-tionsforDSM-5-deÞnedmixedfeatures.CNSSpectrSM.Mixed-upabouthowtodiagnoseandtreatmixedfeaturesinmajordepressiveepisodes.CNSSpectr6.AmericanPsychiatricAssociation.Diagnosticandstatis-ticalmanualofmentaldisorders(4thedn,TextRevision).Washington,DC:AmericanPsychiatricAssociation,7.AmericanPsychiatricAssociation(2013)Diagnosticandstatisticalmanualofmentaldisorders(5thedn).WashingtonDC:AmericanPsychiatricAssociation,M.MixedstatesinDSM-5:implicationsforclinicalcare,education,andresearch.JAectDisordRB.Apragmaticapproachtothediagnosisandtreatmentofmixedfeaturesinadultswithmooddisorders.CNSSpectr2016;LV.Theprevalenceofmixedepisodesduringthecourseofillnessinbipolardisorder.ActaPsychiatrScandR.ThestateoftheartoftheDSM-5withmixedfeaturesŽspeciÞer.ScientiÞcWorldJournalDSetal.Thepreva-lenceandillnesscharacteristicsofDSM-5-deÞnedmixedfeaturespeciÞerŽinadultswithmajordepressivedisorderandbipolardisorder:resultsfromtheInternationalMoodDisordersCollaborativeProject.JAectDisordK.ExclusionofoverlappingsymptomsinDSM-5mixedfeaturesspeci-Þer:heuristicdiagnosticandtreatmentimplications.CNSSpectr2017;T.DSM-5-deÞnedmixedfeaturesŽandBenazzismixeddepression:whichispracticallyuse-fultodiscriminatebipolardisorderfromunipolardepres-sioninpatientswithdepression?PsychiatryClinNeurosci2015;W-M.Prevalenceratesandclini-calimplicationsofbipolardisorderwithmixedfea-turesŽasdeÞnedbyDSM-5.JAectDisordLGetal.Bipolarmixedfea-resultsfromthecomparativeeectivenessforbipolardisorder(BipolarCHOICE)study.JAectDis-ord2017;Mixedstatesandfeaturestreatmentreview J-Metal.Mixedfeaturesinpatientswithamajordepressiveepisode:theBRIDGE-II-MIXs

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