Antipsychotic drugs - cunicz抗精神病药物cunicz

AntipsychoticdrugsPositiveSymptomsHallucinationsDelusions(bizarre,persecutory)DisorganizedThoughtPerceptiondisturbancesInappropriateemotionsNegativeSymptomsBluntedemotionsAnhedoniaLackoffeelingCognitionNewLearningMemoryMoodSymptomsLossofmotivationSocialwithdrawalInsightDemoralizationSuicideSchizophrenia-symptomsFUNCTIONPositive/activesymptomsincludethoughtdisturbances,delusions,hallucinationsNegative/passivesymptomsincludesocialwithdrawal,lossofdrive,diminishedaffect,paucityofspeech.impairedpersonalhygieneDSM-IVDiagnosisSchizophreniaSymptoms>6monthsSchizophreniformdisorderSymptoms1month-6monthsBriefpsychoticdisorderSymptoms1day-1monthPrevalenceofSchizophrenia1-2%ofU.S.population2milliondiagnosedinU.S.Medianageatdiagnosis=mid-20’sMen=WomenprevalenceMenearlierdiagnosisWorsepremorbidhistoryWorseprognosisPrognosisofSchizophrenia10%continuoushospitalization<30%recovery=symptom-freefor5years60%continuedproblemsinliving/episodicperiodsEtiologyHereditaryInfluencesmayaccountfor10%ofschizophreniacasesPrenatalBiologicalTrauma5-10%casesofschizophreniaPerinatalbiologicaltraumaDiathesis-StressModelBiologicalTreatmentInsulincomatherapy,Prefrontallobotomy,ElectroconvulsivetherapyDr.EgasMoniz–Developedprefrontallobotomytechnique1935–heardaboutworkonachimp“Becky〞–Performedsurgeryonmanypatientstheywerejustcalmer,butalsomoresluggishandapatheticAwardedtheNobelPrizeinPhysiologyandMedicineNext15years-50,000lobotomiesSchizophreniaPathophysiology Schizophrenia Pharmacologic

Pathophysiology ProfileofAPDsPast Excessdopaminergic DopamineD2-receptor

activity antagonistsPresent Renewedinterestinthe Combined5-HT2/D2

roleofserotonin(5-HT) antagonistsFuture

Imbalanceincortical Moreselectiveantagonists

communicationand Mixedagonist/antagonists cortical-midbrain Neuropeptideanalogs

integration,involving

multipleneurotransmitters DopaminergicPathwaysandInnervationSchizophrenia-DopamineHypothesisRepeatedadministrationofstimulants

likeamphetaminesandcocaine,whichenhancecentraldopaminergic

neurotransmission,cancauseapsychosisthatresemblesthe

positivesymptomsofschizophreniaLowdosesofamphetaminecaninduceapsychoticreactioninschizophrenicsinremissionStress,amajorpredisposingfactorinschizophrenia,canproduceapsychoticstateinrecoveredamphetamineaddicts.CarlssonandLindqvist(1963)firstproposedthatdrugssuchaschlorpromazineandhaloperidolalleviateschizophrenicsymptomsbyblockingDAreceptorsandtherebyreduceDAfunction.Thessantipsychotic

medications,whichhave

beenthemainstayfortreatmentfornearly50years,havein

commontheirabilitytoblockdopamineD2receptorsAstrongcorrelationbetweentheaffinityofantipsychoticdrugsforDAreceptorsandtheirclinicalpotencyButnoclearandconsistentabnormalityinDAfunctionhasbeendetectedinschizophrenicpatients.SomeearlystudieswithpostmortemtissuerevealedincreasednumbersofDAreceptors(inparticularD2-like)inschizophrenicpatients,butthereareseriousproblemswiththesefindings.Butlong-termadministrationofantipsychoticsproducesincreasesinD2receptorsinanimals.Thereductionincorticaldopaminetransmission(bothatthepre-andpostsynapticlevel)inthechronicPCPmodelseemstobeconsistentwithsomefindingsinschizophrenicpatientsReducedcorticaldopaminetransmissioninducedbylong-termPCPexposuremaybeassociatedwithahyperactivityofsubcorticaldopaminesystemsSchizophrenia-DopamineHypothesisOthertransmittersystemsinvolved..Glutamatergicsystemdysfunctione.g.effectofphencyclidine–blockerofNMDAtypeofglutamatereceptorsG-proteinsignalingabnormalitiesSerotoninergicsystemabnormalitiesmostantipsychoticsalsoaffectserotoninreceptors

DopamineandserotonintheoryofschizophreniaSerotonergicPathwaysandInnervationHypo=hypothalamus

SN=substantianigra

Thal=thalamuscorrelationbetweenDAaffinityandantipsychoticefficacyhasbecomeweakerasaresultofrecentlydevelopedatypicalantipsychoticmedicationsthatalsoshowsubstantialaffinityfor5HT2receptors

Alterationof5-HTtransmissioninthebrainsofschizophrenicspatientshavebeenreportedinpost-mortemstudiesandserotonin-agonistschallengestudiesTherearewidespreadandcomplexchangesinthe5-HTsysteminschizophrenicspatientsThesechanges

suggestthat5-HTdysfunctionisinvolvedinthepathophysiologyofthediseaseSchizophrenia-SerotoninHypothesisPrefrontalCortexLimbic

SystemGABA/AChStriatumVentralTegmentalArea

(A10)SubstantiaNigra

(A9)Dorsal

RapheMedian

Raphe5-HT2AantagonistsreleasedopaminefrominhibitionanddecreaseEPSBlockadeofD2receptors

byconventionalAPDs

causesEPSMotorOutputsGABA

GlutamateDopamine(DA)Serotonin(5-HT)Serotonin-DopamineInteractionsSerotonin-DopamineInteractions:BehavioralStudiesAmphetamine-InducedandSpontaneousLocomotorActivitySerotonindepletion(tryptophan-freediet,lesionsby5,6-dihydroxytryptamine)enhancesamphetamine-inducedhyperlocomotionSerotonindepletionorlesionsofmidbrainrapheincreasespontaneouslocomotoractivityCatalepsyInhibitionofserotonininducedbyelectrolyticlesionsoftheraphe,administrationof5-HTantagonistsdecreasesneuroleptic-inducedcatalepsy

Serotonergicenhancementviatheadditionof5-HTagonists,precursors,anduptakeinhibitorsincreasesneuroleptic-inducedcatalepsyPreclinicalaswellasclinicalstudiesprovideevidenceofhypofunctionofNMDAreceptorsas

aprimary,oratleast,acontributoryprocessinthepathophysiology

ofschizophreniaSeveralclinicaltrialswithagents

thatactattheglycinemodulatorysiteontheNMDAreceptor

haverevealedconsistentreductionsinnegativesymptomsand

variableeffectsofcognitiveandpositivesymptomsThesestudies

alsoprovideevidencethatsuggeststheeffectsofclozapine

onnegativesymptomsandcognitionmaybethroughactivation

oftheglycinemodulatorysiteontheNMDAreceptor.

Schizophrenia-GlutamateHypothesisLimbic

SystemVentralTegmentalArea

(A10)SubstantiaNigra

(A9)Dorsal

RapheMedian

RaphePrefrontal

CortexStriatumNMDAantagonistselevateextracellularbrainlevelsof5-HTintheprefrontalcortexNMDAantagonistsreduceburst

firingofVTADAneuronsNMDAantagonistsincreasethefiringofDAinlimbicareas5-HT2Aantagonistsrestoredopaminergic

functionintheprefrontalcortex5-HT2antagonistsblockthe

effectsofNMDAantagonistsDopamine

(DA)GlutamateSerotonin

(5-HT)GABASerotonin-Glutamate-DopamineInteractionsANIMALMODELOFSCHIZOPHRENIAHighdosesofamphetamineproduceasyndromeofrepetitivebehaviours(sniffing,headmovements,gnawingandlicking)knownasstereotypyorstereotypedbehaviour.Becausestereotypedbehaviouralsooccursinhumansafterhigherdosesofamphetamineandissimilartotherepetitionsofmeaninglessbehaviourseeninschizophrenia,theamphetamine-inducedstereotypyhasbeenusedasananimalmodelofschizophrenia.DAreceptorantagonistsblockamphetaminestereotypyandthereisastrongcorrelationbetweentheirpotencyinthismodelandinamelioratingschizophrenicsymptoms.Othermorecomplicatedmodelsarebasedonattentionalandcognitiveabnormalitiesobservedinschizophrenia.Binder2001ANTIPSYCHOTICSPre-90’s“Typical〞,conventional,traditionalneuroleptics,majortranquilizorsModeledonD2antagonismEPS/TDPost-90’s“Atypical〞,novel,2ndgenerationModeledon5-HT2/D2antagonismLessEPS,prolactineffectsWeightgain,sedation,diabetesImpactofantipsychotics..TypicalantipsychoticsPhenothiazinese.g.chlorpromazine,fluphenazine,thioridazineButyrophenonese.g.haloperidol,droperidolThioxanthinese.g.chlorprotixen,thiothixeneAtypicalantipsychoticsBenzamidesremoxipride(investigational)Diphenylbutylpiperazinese.g.pimozideDibenzodiazepinesClassificationofantipsychoticdrugsAntipsychotics–„classical“Basal-phenothiazinesChlorpromazineThioridazineLevopromazineBasal-thioxanthinesChlorprothixeneIncisive

–phenothiazinesFluphenazineIncisive

–thioxanthinesFlupenthixoleIncisive

–butyrophenonesHaloperidolAntipsychotics–„classical“AdverseEffectsSummarySedation

‑initiallyconsiderable;toleranceusuallydevelopsafterafewweeksoftherapy;dysphoriaPosturalhypotension‑resultsprimarilyfromadrenergicblockade;tolerancecandevelopAnticholinergiceffects‑includeblurredvision,drymouth,constipation,urinaryretention;resultsfrommuscariniccholinergicblockadeEndocrineeffects‑increasedprolactinsecretioncancausegalactorhea;resultsfromantidopamineeffectHypersensitivityreactions‑jaundice,photosensitivity,rashes,agranulocytosiscanoccurIdiosyncraticreactions‑malignantneurolepticsyndromeWeightgainNeurologicalsideeffects-seenextREACTIONFEATURESTIMEOFMAXIMALRISKPROPOSEDMECHANISMTREATMENT

AcutedystoniaSpasmofmusclesoftongue,face,neck,back;maymimicseizures;nothysteria1to5daysUnknownAntiparkinsonianagentsarediagnosticandcurative

AkathisiaMotorrestlessness;notanxietyor"agitation"5to60daysUnknownReducedoseorchangedrug:antiparkinsonianagents,bbenzodiazepinesorpropranololcmayhelp

ParkinsonismBradykinesia,rigidity,variabletremor,maskfacies,shufflinggait5to30daysAntagonismofdopamineAntiparkinsonianagentshelpful

NeurolepticmalignantsyndromeCatatonia,stupor,fever,unstablebloodpressure,myoglobinemia;canbefatalWeeks;canpersistfordaysafterstoppingneurolepticAntagonismofdopaminemaycontributeStopneurolepticimmediately:dantroleneorbromocriptinedmayhelp:antiparkinsonianagentsnoteffective

Perioraltremor("rabbit"syndrome)Perioraltremor(maybealatevariantofparkinsonism)AftermonthsoryearsoftreatmentUnknownAntiparkinsonianagentsoftenhelp

TardivedyskinesiaOral-facialdyskinesia;widespreadchoreoathetosisordystoniaAftermonthsoryearsoftreatment(worseonwithdrawal)ExcessfunctionofdopaminehypothesizedPreventioncrucial;treatmentunsatisfactory

a.Manydrugshavebeenclaimedtobehelpfulforacutedystonia.Amongthemostcommonlyemployedtreatmentsarediphenhydraminehydrochloride,25or50mgintramuscularly,orbenztropinemesylate,1or2mgintramuscularlyorslowlyintravenously,followedbyoralmedicationwiththesameagentforaperiodofdaystoperhapsseveralweeksthereafter.b.Fordetailsregardingtheuseoforalantiparkinsonianagents,seetherestofslidesc.Propranololofteniseffectiveinrelativelylowdoses(20-80mgperday).Selectivebeta1-adrenergicreceptorantagonistsarelesseffective.d.Despitetheresponsetodantrolene,thereisnoevidenceofanabnormalityofCa2+transportinskeletalmuscle;withlingeringneurolepticeffects,bromocriptinemaybetoleratedinlargedoses(10-40mgperday).NeurologicalSideEffectsofantipsychoticsAdverseEffects-EPSDetailsontwomainextrapyramidaldisturbances(EPS):Parkinson-likesymptomstremor,rigiditydirectconsequenceofblockofnigrostriatalDA2RreversibleuponcessationofantipsychoticsTardivedyskinesiainvoluntarymovementoffaceandlimbslesslikelywithatypicalantipsychotics(AP)appearsmonthsoryearsafterstartofAP?resultofproliferationofDARinstriatumpresynaptic?treatmentisgenerallyunsuccessful Phenothiazines-SideeffectsWeightgain–40%-weightgainnowattributedtoratioofbindingtoD2and5-HT2receptors;possiblyalsohistamine(fornewerantipsychoticsanyway)SexualdysfunctionresultfromNEandSEblockadeerectiledysfunctionin23-54%ofmenretrogradeejaculationinlossoflibidoandanorgasmiainmenandwomenSeizures-<1%forgeneralizedgrandmalESTIMATEDMEANWEIGHTGAINAT10WEEKSAllisonDB,MentoreJL,HeoM,etal:Weightgainassociatedwithconventionalandnewerantipsychotics:ameta-Analysis.AJP,1999.PlaceboMolindoneZiprasidoneFluphenazineHaloperidolNon-pharmcontrolRisperidoneChlorpromazineSertindoleThioridazineOlanzapineClozapine012345-1Meanchangeinbodyweight(kg)Acomprehensiveliteraturesearchidentified78studiesthatincludeddataonweightchangeinpatientstreatedwithaspecificantipsychotic.Foreachagentameta-analysisandrandomeffectsregressionestimatedthechangeinweightat10weeksoftreatment.Phenothiazines-SideeffectsNeurolepticmalignantsyndrome(1-2%earlyintrt)combinationofmotorrigidity,hyperthermia,andautonomicdysregulationofbloodpressureandheartrate(bothgoup)canbefatalin5-20%ofcasesifuntreatedtreatment–discontinuemeds;givetrtsforfeverandcardiacproblemsSensitivitytosun

somephenothiazinescollectinskin(chlorpromazine)sunlightcausespigmentationchanges–grayish-purplesplotching(lookbruised)canalsooccurineyeandcausebrownincorneathisproducesabrownishcloudtovisionandpossiblypermanentimpairmentAgranulocytosis-<1%reducedwhitebloodcellcountloweredresistancetoinfectioncanbefatalJaundice–elevatedbilirubininliver-<½%Phenothiazines-DrugInteractionsenzymeinteractionswithbarbiturates(phenobarbital);phenytoin(Dilantin);carbamazepine(Tegretol)–reducephenothiazinelevelsco-administrationmustbecarefullymonitoredtopreventtoxicityenzymecompetitionwithSSRIsincreaseslevelsandmayincreasesideeffectsHaloperidole

enteredUSmarketin1967morepotentthanphenothiazines,sodosesareloweralsohavelonghalf-lifelikephenothiazines,theyblockdopamineandnorepinephrinereceptorsandshowtherelatedsideeffectsextrapyramidaleffectsareworse(duetolowblockadeofAChandthusworseratio)butbloodpressureeffectsarelessreducedsedationnobloodabnormalitiesorjaundiceLimitationsOfConventionalAntipsychoticsApproximatelyone-thirdofpatientswithschizophreniafailtorespondLimitedefficacyagainstNegativesymptomsAffectivesymptomsCognitivedeficitsHighproportionofpatientsrelapseSideeffectsandcomplianceissuesSomesafetyissuesareprominentAntipsychoticDrugs–NewGenerations„atypical“About40-60%donotrespondtophenothiazinesorcannothandlesideeffectsQuestionsremainabouttheefficacyofphenothiazinesandhaloperidolefornegativesymptomsDrugsneededthatarelowinextrapyramidalsideeffectsandatleastequalinefficacyforpositivesymptoms,perhapsbetterfornegativeAntipsychoticDrugs–NewGenerations„atypical“clozapinerisperidoneolanzapinesertindolequetiapineetc.AtypicalantipsychoticsMARTA(multiactingreceptortargetedagents)clozapine,olanzapine,quetiapineSDA(serotonin-dopamineantagonists)risperidone,ziprasidone,sertindoleSelectiveD2/D3antagonistssulpiride,amisulpirideClozapine(1989)SelectivelyblocksdopamineD2receptors,avoidingnigrostriatalpathwayAlsoblocksNEMorestronglyblocks5-HT2receptorsincortexwhichthenactstomodulatesomedopamineactivityAmongnon-responderstofirstgenerationmedsorthosewhocannottoleratesideeffects,about30%dorespondtoClozapineClozapineExtrapyramidalsideeffectsareminimalMayhelptreattarditivedyskinesiaStillshowsorthostatichypotensioneffects,sedation,weightgain,increasedheartrateIncreasedriskforseizures(2-3%)Agranulocytosisin1%Agranulocytosisrisksincreasewhenco-administeredwithcarbamazepineInteractionswithSSRIsandvalproicacidincreaseClozapinelevelsandrisksRisperidone(Risperdal;1994)FewersideeffectsthanClozapineMarketedasfirstlineapproachtotreatmentBlocksselectiveD2,norepinephrine,and5-HT2Arguedaseffectiveforpositiveandnegativesymptoms(controversial)Extrapyramidalsideeffectslow(butareshownathighdoses)-controversialSharessedation,weightgain,rapidheartbeat,orthostatichypotension,andelevatedprolactinNoagranulocytosisrisksMaycauseanxiety/agitation(possibleOCD)Risperidone(Ris