神經(jīng)病理學(xué)醫(yī)學(xué)知識(shí)培訓(xùn)SchizophreniaEmilKraepelin“DementiaPraecox’(1896)Blueler“Schizophrenia”O(jiān)nset:adolescenceoryoungadulthoodDSM-IVreview:Positivesymptoms(delusions,hallucinations,disorganizedspeechorbehavior)Negativesymptoms(catatonia,affectiveflattening,withdrawal,oravolition)Social-occupationaldisturbance6+monthsAssociatedFeaturesCognitiveDisturbancesMemorySensoryfilteringAttentionEmotionrecognitionEye-trackingInterpersonalDysfunctionSubtypesCatatonicParanoidDisorganizedUnlikelytobearelatedtoasinglephysiopathologyNeuropathologyNeurodevelopmentalhypothesisNeurodegenerativehypothesisDopaminehypothessisGlutamatergichypothesis**ThesearenotexclusiveWhatcausesschizophrenia?Heritable(Shastry,2023)EnvironmentalfactorsEpidemiologicalstudiesBirthcomplicationsMaternalstressSeasonalityeffectViralepidemicsLatitudeeffectRhincompatibilityNeuropathology

StructuralalterationsBehavioralsymptomsindicativeofbraindamage(unusualratesofblinking,poorcontrolofeyemovements,unusualfacialexpressions)Enlargedventricles(Weinberger&Wyatt,1982;Andreason)VentricularenlargementinmonozygotictwinwithschizophreniaBarondes,1993HippocampalvolumelossandenlargedventriclesVanHeronetal.,2023Neuropathology

Structuralalterations(cont)Alterationsinnumerousareas,includingfrontallobes,medialtemporallobes,lateraltemporallobes,parietallobe,basalganglia,corpuscallosum,thalamusandeventhecerebellumWhitematterdeficitsEvidenceofdisorganizedneuronsandfailuresofmigrationAltereddensityanddisorganizationofneuronsfoundinthewhitematterbelowlayerVIinthecortexDisorganizedpyramidalcellsinthehippocampusAltereddevelopmentofhippocampalpyramidalneuronsNeurodevelopmentalHypothesisHomemoviesfromfamilieswithschizophrenicchilddisplayedabnormalbehavior(Walkeretal,1994;1996)ChildrenwholaterbecomeschizophrenicexhibitpoorsocialadjustmentandschoolperformanceDevelopmentaldelaysPremorbidpsychopathology(anxiety,depression,conductdisorders,ADHD)(Kim-Cohenetal,2023)Physicalabnormalities(Schiffman,etal.2023)Ratesofconcordancearehigherinmonochorionictwinscompareddichorionictwins(60%vs.11%)(Davis,etal,1995)Butwhyaresymptomsnotobserveduntiladolescence?SomethingmusttriggerthedegenerativeprocessattheperiodofadolescenceLossanddisorganizationofneuronsbecome‘unmasked’withpruningandsynapticreorganizationRapidlossofbrainvolumeduringadolescenceinschizophrenicsThompsonetal,2023Thompsonetal,2023Twinstudy—lossofdlPFCandtemporalcorticaltissueCannonetal2023HypofrontalityReducedactivationofthedorsolateralprefrontalcortexduringacontextprocessing/attentiontaskinfirstepisode/drugna?veschizophrenicsMacDonaldetal.,2023poorlyinnervatedtoxicorgeneticinsultdysfunctiondeathpoorneuronalmigrationinadequatesynapseselection Couldaltereddevelopmentberelatedtoglutamatergicdysfunction?

-Underactivationofsystemsaltersmigration,synapticorganizationandcellsurvival -OveractivationofsystemscanleadtoalteredsynapticconnectivityandcelldeathSPECTRUMOFEXCITATIONBYGLUTAMATEExcessexcitation-Mania-PanicExcitotoxicity-DamagetoneuronsExcitotoxicity-Slowneuro-degenerationExcitotoxicity-CatastrophicneurodegenerationNormalexcitationNeurodegenerativeHypothesisCouldthepsychoticsymptomsthemselvesbeproducingadditionalexcitotoxicity?NeurochemicalAlterationsDopamineHypothesisOriginalFormulationOveractivityofsubcorticalD2receptorscontributestopositivesymptomsClassicalantipsychoticswereDAD2antagonistsDAagonistsinducepsychotogeniceffectshypothalamusdcNucleusaccumbensTegmentumbSubstantianigraBasalGangliaaDOPAMINEPATHWAYSmesolimbicpathwaymesolimbicoveractivity=positivesymptomsofpsychosispureD2blocker11-2StahlSM,EssentialPsychopharmacology(2023)Re-formulationofdopaminehypothesismeso-corticalpathwayAmphetamine-induceddopaminereleaseisenhancedinschizophrenicsLaruelleetal2023Amphetamine-induceddopaminereleaseproducespositivesymptomsLaruelleetal,1996Increaseddopaminereleaseinmedication-na?veschizophrenicpatientsHietala,etal.1995D2receptors?MixeddataSomefindnodifferencesOthersfindmoderateincreases(Kestleretal.,2023)WhataboutD3andD4receptors?WhataboutthemesocorticalDAsystem?OnepostmortemstudyindicatedadecreaseinDAinnervationofthedorsolateralprefrontalcortex(Akil,etal1999)TwoPETstudieshadmixedfindings,buttheligandsusedforD1receptorswerenotselective(Okuboetal1997;Karlssonetal2023)Morerecently,thereisevidenceofanupregulationofD1receptorsintheDLPFCIncreasedD1receptoravailabilityinschizophrenicssuggestsunderactivationAbi-Darghametal,JNeurosci,2023IncreasesinD1receptoravailabilityintheDLPFCarecorrelatedwithworkingmemorydeficitsAbi-Darghametal,JNeurosci,2023ReductionindendriticspinesindopaminergicneuronsinthedorsolateralprefrontalcortexLewisetal,2023GlutamateHypothesisDeficienciesinglutamatergicneurotransmissionDysregulationofDAsystemsmaybesecondarytoadeficitinthefunctionoftheglutamatergicNMDAreceptorGlutamateHypothesisEvidencefromhumanstudiesAlterationsinCSFglutamatelevels,alteredglutamatemetabolismandalteredNMDAreceptorsubunitgeneexpression(Keshavan,1999)DirectevidenceisstilllackingandacoherentpicturehasnotyetemergedLackofadequateradioligandstovisualizetheGLUsysteminthelivingbrainisamajorimpedimentGlutamate-DopamineInteractionsLaruelleetal,2023ChronicPCPtreatmentreducesdorsolateralprefrontalcortexdopamineandleadstonegativesymptomsHumanstudiesAnimalstudiesJentschandRoth,1999ChronicPCPleadstobehavioraldeficitsconsistentwithdorsolateralprefrontalcortexdysfunctionJentschetal,Science,1997ChronicPCPreducescorticaldopamineJentschetal,Science,1997EffectsarereversedwithclozapineJentschetal,Science,1997NMDAreceptorantagonismenhancesamphetamine-inducedsubcorticalDAreleaseKegellesetal2023ReducedprefrontalcortexactivationinschizophrenicsMeyeretal.,2023ReduceddlPFCactivationwasnegativelycorrelatedwithstriataldopaminereleaseMeyeretal.,2023SubcorticalDopamine-GlutamateInteractionsGABAalterationsGlutamateorGABA?PutitalltogetherNeurodevelopmentalbraindamage,leadstodysfunctioninareasliketheprefrontalcortex,whichleadstoincreasedDAinthemesolimbicareasWhataboutthetemporallobedamage?Hippocampusandamygdalacontrolagatethatinfluencestheeffectsoftheprefrontalcortexonn.accumbensneuronalfiringThisgatemodulatesreactionsofthen.accumbensgiventhecontextHippocampusmaymodulateprefrontalactivationofn.accumbensGrace,2023Grace,2023HowdoesexaggerationsofmesolimbicDAactivityleadtopositivesymptoms? Couldaltereddopamineinthenucleusaccumbensalterthesalienceattributedtointernalandexternalstimuli? KapurreadingTreatmentsConventionalneurolepticsChlorpromazineHaloperidolLoxapinePimozideThieoridazinethirothixenepureD2blockerTypicalantipsychoticsareD2receptorantagonists

Blockadeofreceptorsinthenigrostriataldopaminepathwaycausesthemtoup-regulateThisup-regulationmayleadtotardivedyskinesiaConventionalantipsychoticshaveothersitesofactionMuscariniccholinergicblockadeSideeffectsofconstipationandblurredvisionReducethelikelihoodofextrapyramidalsymptomsProblemswithconventionalantipsychoticsBecauseofsideeffects,manypatientsdiscontinuetreatments,relapse,gobackontreatmentrepeatedlyNeurolepticmalignantsyndromeAtypicalantipsychoticdrugsSerotonin-dopamineantagonistsClozapineRisperidoneOlanzapineQuetiapineZiprasidone5HT-DAInteractionsSubstantianigraraphenucleusbrakebrakeserotoninneurondopamineneuronSubstantianigraRaphedopamine5HT2Areceptorserotonin5HT2AreceptorserotoninneurondopamineneuronSubstantianigraRaphedopamine5HT2Areceptorserotonin5HT2Areceptor11-19StahlSM,EssentialPsychopharmacology(2023)serotoninneurondopamineneuronSubstantianigraRaphe5HT2Areceptor11-20StahlSM,EssentialPsychopharmacology(2023)DAneuron5HTneuronpostsynapticneurondopamineD2receptor5HT2AreceptorNigrostriatalpathwayserotoninNigrostriatalpathwaynodopaminerelease11-22StahlSM,EssentialPsychopharmacology(2023)SDAD2receptor11-23StahlSM,EssentialPsychopharmacology(2023)Nigrostriatalpathway5HT2AreceptorNigrostriatalpathway11-24StahlSM,EssentialPsychopharmacology(2023)conventionalantipsychoticcaudatenucleusserotonin-dopamineantagonistcaudatenucleusmesocorticalpathwayprimarydopaminedef