resistant

Therapy-ResistantSchizophrenia

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AdvancesinBiologicalPsychiatry

Vol.26

SeriesEditors

reiburg

rOxford

SãoPaulo

aUlm/Ravensburg

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Therapy-Resistant

Schizophrenia

VolumeEditors

HelioElkisSãoPaulo

rNashville,Tenn.

5figuresand14tables,2010

Bal·Freiburg·Paris·London·NewYork·Bangalore·

Bangkok·Shanghai·Singapore·Tokyo·Sydney

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blicationislistedinbibliographicrvices,includingCurrentContents®andIndexMedicus.

tements,opinionsanddatacontainedinthispublicationaresolelythooftheindividualauthorsand

contributorsandnotofthepublisherandtheeditor(s).Theappearanceofadvertimentsinthebookisnotawarranty,

endorment,orapprovaloftheproductsorrvicesadvertidoroftheireffectiveness,lisherandthe

editor(s)disclaimresponsibilityforanyinjurytopersonsorpropertyresultingfromanyideas,methods,instructionsorproducts

referredtointhecontentoradvertiments.

horsandthepublisherhaveexertedeveryefforttoensurethatdruglectionanddosagetforthinthis

textareinacr,inviewofongoingrearch,

changesingovernmentregulations,andtheconstantflowofinformationrelatingtodrugtherapyanddrugreactions,thereader

isurgedtocheckthepackageinrtforeachdrugforanychangeinindicationsanddosageandforaddedwarningsand

particularlyimportantwhentherecommendedagentisanewand/orinfrequentlyemployeddrug.

ofthispublicationmaybetranslatedintootherlanguages,reproducedorutilizedinanyformorby

anymeanlectronicormechanical,includingphotocopying,recording,microcopying,orbyanyinformationstorageand

retrievalsystem,withoutpermissioninwritingfromthepublisher.

©AG,,CH–4009Bal(Switzerland)

PrintedinSwitzerlandonacid-freeandnon-agingpaper(ISO9706)byReinhardtDruck,Bal

ISSN0378–7354

ISBN978–3–8055–9511–7

e-ISBN978–3–8055–9512–4

LibraryofCongressCataloging-in-PublicationData

Therapy-resistantschizophrenia/volumeeditors,HélioElkis,HerbertY.

Meltzer.

p.;cm.--(Advancesinbiologicalpsychiatry,ISSN0378-7354;v.

26)

Includesbibliographicalreferencesandindexes.

ISBN978-3-8055-9511-7(hardcover:)

,Hér,:Advances

inbiologicalpsychiatry,v.26.0378-7354;

[DNLM:ychotic

Resistance.W1AD44v.262010/WM203T3982010]

RC514.T4662010

362.2Ј6--dc22

2010014932

lkis

tituteofPsychiatry

UniversityofSãoPaulo

MedicalSchool

SãoPaulo(Brazil)

r

hiatry

VanderbiltUniversity

SchoolofMedicine

Nashville,TN(USA)

AdvancesinBiologicalPsychiatry

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SectionTitle

Contents

VIIPreface

Elkis,H.(SãoPaulo);Meltzer,H.Y.(Nashville,Tenn.)

ConceptsandAsssment

1HistoryandCurrentDefinitionsofTreatment-ResistantSchizophrenia

Elkis,H.(SãoPaulo)

9AsssmentofTherapy-ResistantSchizophrenia

Lindenmayer,J.P.;Khan,A.(NewYork,N.Y.)

33NeuropsychologyofTreatment-ResistantSchizophrenia

Woodward,N.D.;Meltzer,H.Y.(Nashville,Tenn.)

EtiologyandNeurobiology

52GeneticStudiesinTreatment-ResistantSchizophrenia

DeLuca,V.;Souza,R.P.;Panariello,F.(Toronto,Ont.);Meltzer,H.Y.(Nashville,Tenn.)

63NeuroimagingofTreatment-ResistantSchizophrenia

Borgio,J.G.;Rocha,D.;Elkis,H.;Bressan,R.A.(SãoPaulo)

74DurationofUntreatedPsychosisandPremorbidFunctioning:Relationshipwith

TreatmentResponandTreatment-ResistantSchizophrenia

Bobo,W.V.;Meltzer,H.Y.(Nashville,Tenn.)

DiaManagementandTreatmentStrategies

87DiaManagement:MultidimensionalApproachestoIncompleteRecovery

inPsychosis

Lambert,T.J.(Sydney)

114RoleofClozapineinTreatment-ResistantSchizophrenia

Meltzer,H.Y.(Nashville,Tenn.)

129AugmentingClozapineResponinTreatment-ResistantSchizophrenia

Remington,G.(Toronto,Ont.)

152NewTherapeuticStrategiesforResistancetoClozapineand

Treatment-ResistantSchizophrenia

Souza,J.S.;Kayo,M.;Neto,J.H.;Elkis,H.(SãoPaulo);Buckley,P.F.(Augusta,Ga.)

165ElectroconvulsiveTherapyforTreatment-RefractorySchizophrenia

Chanpattana,W.(Bangkok)

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VIContents

177TreatmentofTherapy-ResistantAuditoryVerbalHallucinationsin

SchizophreniaPatientsbyRepetitiveTranscranialMagneticStimulation

Jandl,M.;Kaschka,W.P.(Ulm/Ravensburg)

195AuthorIndex

197SubjectIndex

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Preface

Itiswellknownthatupto30%ofpatientswithschizophreniadonotrespondto

treatmentwithantipsychoticdrugsthatareusuallyeffective,inatleastinimprov-

ent-resistantschizophrenia(TRS)reprentsaneven

greaterburdenforaffectedpatients,lume

ofAdvancesinBiologicalPsychiatryisdedicatedtoacomprehensiveanalysisofTRS,

withreviewsoftheconcept,asssment,neurobiologyandtreatment.

-term

(15–25years)multicenterepidemiologicalstudiespromotedbytheWorldHealth

Organizationshowedthat50%ofpatientswithpsychosishaveapooroutcome[1].A

meta-analysisoftheliteratureencompassingacenturyofschizophreniatreatment–

biological,surgicalandpsychopharmacological–showedthatpatientswithfavorable

outcomereprentonly40%ofcas[2].TRSasdefinedinthisvolumereprents

onlyasubtofpoor-outcomeschizophrenia,ithpersistentmoderate-to-

tcomecanevenoccurinschizophrenicpatients

withgoodcontrolofpsychoticsymptomsbecauofthefunctionaleffectsofcogni-

tiveimpairment,negativesymptomsandmoodsymptomsthatareindependentof

positivesymptoms.

Thediscoveryofchlorpromazineinthe1950sledtothefirsteffectivetreatment

forpositivesymptomsinthemajorityofpatientswithschizophrenia,eventhowho

lowedmassivedischargesfrompublicandpri-

vatementalhospitals,enablingpatientstobegincommunityresidenceandtreatment.

However,agroupofpatientscontinuedtohavepersistentdelusionsorhallucinations,

orboth,atientsare

correctlyreferredtoasbeingtreatmentresistanttotheso-calledtypicalantipsychotic

drugs(sometimesreferredtoasfirst-generationdrugs)[3].Withtheexceptionofclo-

zapine,noneofthenewerantipsychoticdrugs(picalantipsychoticdrugs,

suchasrisperidoneandolanzapine)udatconventionaldosareabletotreatthe

majorityofsuchpatients,althoughsomedorespond,suggestingheterogeneityinthis

classofpatients.

AspointedoutbyLindenmayerinthisissue,TRScanhaveadevastatingeffecton

individualsandfamilies,reprentingasignificantpublichealthproblem.

SectionTitle

VII

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VIIIPreface

Despitethepersistenceofpositivesymptoms(whichbydefinitionmeansTRS),

cliniciansoftenfailtomaketheappropriatediagnosisandclinicaldecision,which

wouldbetosuggestclozapinetreatment,theonlydrugthatisapprovedforTRS.

Thereare,ofcour,manyothertreatmentswhichhavebeenudandareoccasion-

archisneededtoprovideadditionaltreatmentsforTRS,as

clozapinehasanumberofrioussideeffectsandisineffectiveinaboutonethirdof

perasssmentandmanagementofTRSisfullydiscusdinthe

chaptersbyLindenmayer&KhanandLambertinthisvolume.

ncludetheduration

ofuntreatedpsychosis,asreviewedbyBoboandMeltzer,buttheevidenceforitsrel-

cfactorsareconsideredbyDe

Lucaetal.,whilebrainstructuralandfunctionalabnormalities,asdescribedbyBorgio

issue,arealsoimportantinthepathophysiologyofTRSandmaybegenetic

otduetocognitiveimpairment,asthisisfoundwithequalverity

detailedinthechapterbyWoodwardandMeltzer.

ThelandmarkstudyofKaneetal.[4]showedthatclozapinewassuperiortochlo-

rpromazine,atypicalantipsychoticdrug,inpatientswithTRSasdefinedhere,not

simplyawastebasketon‘poorrespon’.Thevalidityofthisstudyhasbeencon-

firmedworldwide,butdespitethis,theuofclozapineismuchlessthanitshould

5%ofpatientswithschizophreniaintheUSAreceiveclozapine,whichhas

alsobeenindicatedtoreducetheriskofsuicide[5,6].ChinaandFinlandaretwo

tedoutbyMeltzerinthisissue,

clozapineisstillconsideredtobethemosteffectiveofallantipsychoticdrugs,despite

theintroductionofmanynewclassofantipsychoticsandconsiderableadvances

iteduisduetoanexaggeratedfearoftheriskof

agranulocytosis,aswellasveryrealsideeffectssuchastachycardia,sialorrhea,i-

zures,myocarditis,weightgain,typeIIdiabetesandOCDsymptoms.

P

additionofotherantipsychoticdrugsisusuallyineffective,whereasECTisoftenhelp-

ptersinthisvolumebyRemington,Champattana,JandlandKaschka,and

efulldiscussionsofpharmacological,aswellasnon-pharmacolog-

ical,strategiestoprovidesupplementaltreatmentsforclozapineinTRSpatients.

Wewouldliketothankallourcolleaguesfordevotingthemlvesforextended

ttheircollaboration,

lthanksshouldbegiventothestaffof

Karger,especiallytoGunhildWolfandGabriellaKarger.

Finally,wewouldliketothankstheeditors,Ebert,Ebmeier,Kaschkaand,inpar-

ticular,Gattaz,whonotonlyprovideduswiththisuniqueopportunity,

butalsogavehixpertguidanceinallphasofthisproject.

HelioElkis,SãoPaulo

r,Nashville,Tenn.

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PrefaceIX

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