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Schizophrenia

Dr.FredRose

NatureofSchizophreniaandPsychosis:AnOverview

•  Schizophreniavs.Psychosis–  Psychosis–Clusterofdisorders;hallucina5onsand/orlossofcontactwithreality

–  Schizophrenia–Atypeofpsychosis

•  Affects1in100persons,$65Billionannually•  HistoricalBackground

–  EmilKraeplin–1896;Usedthetermdemen5apraecox,focusedononsetandoutcomes

–  EugeneBleuler–1911heintroducedtheterm“schizophrenia”or“spliJngofthemind”

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PrevalenceofSchizophrenia•  Prevalenceof1%worldwide

–  2×Alzheimer’s–  5×Mul5pleSclerosis–  6×Insulin‐dependentDiabetes–  60×MuscularDystrophy

•  SchizophreniaIsGenerallyChronic– Moderate‐to‐severelifelongimpairment

–  Lifeexpectancyisslightlylessthanaverage

•  EqualGenderDistribuLon– Women‐beWerlong‐termprognosis

–  Onsetdiffersbetweenmenandwomen

Gender differences in onset of schizophrenia in a sample of 470 patients

Howard et al., 1993

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Diagnosis:DSMIV•  Symptoms(2ormore):

–  Delusions(content)–  Hallucina5ons–  Disorganizedspeech(form)–  Disorganizedorcatatonicbehavior–  Nega5vesymptoms(flataffectetc.)

•  Social/Occupa5onalDysfunc5on

•  Dura5on:6‐months(1monthofsymptoms)

•  Notcausedbysubstances

•  NotSchizoaffec5ve/MoodDisorder

The“PosiEve”Symptoms

•  Ac5vemanifesta5onsofabnormalbehaviorordistor5onsofnormalbehavior

•  Delusions‐90%– Soma5c:“Snakelivinginsidemyabdomen”

– Grandeur:“ChosenbyGod”– Persecu5on:“‘They’aremonitoringme”

– Manifesta5ons:Thoughtbroadcas5ng,ideasofreference,thoughtwithdrawal

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The“PosiEve”SymptomCluster

•  HallucinaLons– Sensoryeventswithoutenvironmentalinput

– Auditoryarethemostcommon(canbeanysensorymodality)

– Normalvolume,known,external,nega5ve

– Speechvs.auditoryprocessingstudies

Some major language areas of the cerebral cortex

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The“NegaEve”SymptomCluster

•  Absenceorinsufficiencyofnormalbehavior

•  SpectrumofNegaLveSymptoms

–  Avoli5on(orapathy)–Inabilitytoini5ateandpersistinac5vi5es

–  Alogia–Arela5veabsenceofspeech

–  Anhedonia–Inabilitytoexperiencepleasureorengageinpleasurableac5vi5es

–  Flataffect–ShowliWleexpressedemo5on,butmays5llfeelemo5on

“Disorganized”Symptoms

•  Severeandexcessdisrup5onsin:•  Speech

– Cogni5veslippage–Illogicalandincoherentspeech

– Tangen5ality–“Goingoffonatangent”andnotansweringaques5ondirectly

– Looseassocia5onsorderailment–Takingconversa5oninunrelateddirec5ons

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“Disorganized”Speech

“Ihavealsokilledmyex‐wife,[name],ina2.5to3.0hourssexboutinDevonPennsylvaniain1976,whiletwoPitcairnswereresidinginmynextroomcloset,hearingtheevent.Enclosed,pleasefindmyurologyreport,indica5ngthatmymalegenitals,specificallymypenis,arewithinnormalsizeandthatI’mcapableofnormalintercoursewithanywoman,signedbyDr.[name],aurologistandsurgeonwhoperformedacircumcisiononmein1982.Conclusions:Icannotbeanincompoopinaphysicalsense(unlessSocietywouldfeedmechemicalsformypictureinthenincompoopbook).”

“Disorganized”Symptoms

•  Affect–  Inappropriateaffect(e.g.,cryingwhenoneshouldbelaughing)

•  Behavior– Disrup5oningoaldirectedbehavior– Declineinrou5nedailyfunc5oning– Catatonia–Spectrumfromwildagita5on,waxyflexibility,tocompleteimmobility

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SymptomsofSchizophreniaPositive (Type 1)

Negative (Type II)

Disorganized

Thematic Delusions Avolition (apathy) Grossly Bizarre Behavior

Thematic Hallucinations Alogia (Poverty of Speech/Content)

Incoherent hallucinations or delusions

Bizarre Behavior Anhedonia Disorganized Affect

Flat Affect Disorganized Speech

Asociality

Lenzenweger, Dworkin & Wethington (1991)

SubtypesofSchizophrenia•  ParanoidType

–  Intactcogni5veskillsandaffect,anddonotshowdisorganizedbehavior

–  Hallucina5onsanddelusionsthema5c(e.g.,grandeurorpersecu5on)

•  DisorganizedType– Markeddisrup5onsinspeech,behavior,affect

–  Fragmentedhallucina5onsanddelusions

–  Developsearly,tendstobechronic,lacksperiodsofremissions

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Subtypes(cont.)

•  CatatonicType–  Unusualmotorresponsesandoddmannerisms(e.g.,echolalia,echopraxia)

–  ?Needforconsistency–  Tendstobesevereandquiterare

•  UndifferenLatedType–  Symptoms,butdon’tmeetcriteriaforanothertype

•  ResidualType–  Onepastepisodeofschizophrenia–  Con5nuetodisplaylessextremeresidualsymptoms(e.g.,oddbeliefs)

ProblemswithDiagnosis

•  Heterogeneityofsymptoms– Symptomschangeasthedisorderdevelops– Schizophrenics‘slipbackintoreality’

•  Treatementresponsevaries•  Isitaunitarydisorder?•  IsitdisLnctfromnormalexperience?

“Schizophrenia appears to be a disorder with no particular symptoms, no particular course, no particular outcome and which responds to no

particular treatment” [Bentall, 1990]

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OtherPsychoEcDisorders

•  SchizophreniformDisorder– Schizophrenicsymptomsforlessthan6months– AssociatedwithgoodpremorbidfuncEoning;mostresumenormallives

•  Schizoaffec3veDisorder– Symptomsofschizophreniaandamooddisorder– 10‐yearoutcomebeQerthanSchizophrenia(Harrowetal.,2000)

OtherPsychoEcDisorders

•  DelusionalDisorder– Delusionswithoutothermajorschizophreniasymptoms

– MayshowothernegaEvesymptoms

– Typeofdelusionsincludeerotomanic,grandiose,jealous,persecutory,andsomaEc

– ThiscondiEonisextremelyrare

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AddiEonalDisorderswithPsychoEcFeatures

•  BriefPsychoLcDisorder–  Oneormoreposi5vesymptomsofschizophrenia

–  Usuallyprecipitatedbyextremestressortrauma

–  Lasts<1month

•  SharedPsychoLcDisorder–  Delusionsfromonepersonmanifestinanotherperson

–  LiWleisknownaboutthiscondi5on•  SchizotypalPersonalityDisorder

– Mayreflectalesssevereformofschizophrenia

GeneEcsInfluences•  FamilyStudies

–  Inheritatendencyforschizophrenia–  Schizophreniaincreasesriskinotherfamilymembers

•  TwinStudies–  RiskofschizophreniainMZtwinsrangesfrom15%to65%,withanaverageof28%(Fuller‐Torrey,1994).

–  Riskofschizophreniadropsto6%fordizygo5ctwins•  AdopLonStudies

–  Riskremainshighinadoptedchildrenwithabiologicalparentsufferingfromschizophrenia

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GoQesman,1991

Risk of developing schizophrenia

GeneEcInfluences(cont.)

•  SummaryofGeneLcResearch

– Riskofschizophreniaincreasesasafunc5onofgene5crelatedness

– Mul5plegenesinvolved

– Oneneednotshowsymptomsofschizophreniatopassonrelevantgenes

– Schizophreniahasastronggene5ccomponent,butgenesalonearenotenough

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GeneEcInfluences(cont.)

•  GenesscaWered15of23chromosomeshavebeenimplicated

•  Mostimportant:–  Neuregulin1:NMDA,GABA,&Achreceptors–  Dysbindin:synap5cplas5city–  Catechol‐O‐methyltransferase:DAmetabol.–  G72:regulatesglutamatergicac5vity

–  Others:myelina5on,glialfunc5on

•  Paternalage:morecelldivisionsinsperm

BiologicalMarkers

•  Smooth‐PursuitEyeMovement

– Trackingamovingobjectvisuallywiththeheadkepts5ll

– Trackingisimpairedinpersonswithschizophrenia,includingtheirrela5ves

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EEology

•  TheDopamineHypothesis– Overac5vityofdopamine(DA)neuronsinthebraincausesschizophrenia

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TheDopamineHypothesis•  Support

– Drugsthatblockdopaminereceptorsreduceposi5vereceptors

– Amphetamines,whichincreasedopamine,createposi5vesymptoms

– HighnumberofD2receptorsinschizophrenicbrains

TheDopamineHypothesis•  Problems

– Dopamineantagonistsdon’ttreatnega5vesymptoms

– Timelapse‐immediatelyinbrainbutnoimprovementfor2weeks

– Parkinson’sdisease(but…)•  Substan5a‐Nigra,Caudate‐Putamen‐PD•  VentralTegmentum,NucleusAccumbens,Septalarea‐Schiz.

– Neurolep5csincreaseD2receptors– PETscanstudiesinconclusive

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TheDopamineHypothesis

•  Revised:– Overac5vityofdopamineneuronsinthemesolimbicpathwaymaycauseposi5vesymptoms.•  An5psycho5cswhichblockdopaminereceptorslessenposi5vesymptoms

– but…

TheDopamineHypothesis

•  Revised:– Underac5vityofdopamineneuronsinthemesocor5calpathwayintheprefrontalcortexmaycausenega5vesymptoms.•  An5psycho5cshaveliYleornoeffectonnega5vesymptoms.

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DopaminePathways

OtherNeurobiologicalInfluences

•  StructuralandFuncLonalAbnormaliLesintheBrain– Enlargedventriclesandreduced5ssuevolume

•  Inverserela5onshipbetweenventriclesizeandresponsetomedica5on

– Abnormalneuralmigra5on

– GraymaWerlossinadolescence

– Hypofrontality–Lessac5vefrontallobes(amajordopaminepathway)

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EnlargedVentriclesinSchizophrenia

Source: Daniel Weinberger, M.D.

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FuncEonalchangesinbrain

•  Hypofrontalityhypothesis– Discordanttwins:lowfrontalbloodflowonlyinaffectedtwin

– CogniEveFlexibility•  Schizophrenicscan’tshi_aQn.toothercriterion•  FuncEonalimaging:frontallobeacEvityloweratrest,esp.inrighthemisphere,doesnotincreaseduringtask.

•  DrugtreatmentincreasedacEvaEonoffrontallobes

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PsychosocialInfluences

•  TheRoleofStress– Mayac5vateunderlyingvulnerabilityand/orincreaseriskofrelapse

•  FamilyInteracLons

–  Familiesofpeoplewithschizophreniashowineffec5vecommunica5onpaWerns

–  Highexpressedemo5oninthefamilyisassociatedwithrelapse

•  TheRoleofPsychologicalFactors–  Likelyexertonlyaminimaleffectinproducingschizophrenia

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Gene‐EnvironmentInteracEon

•  Tienarietal.(1985,1987);Tienari(1991,1994)– Childrenofschizophrenicand“normal”mothersadoptedoutatbirth)

– TrackedfamilycommunicaEonpaQerns

High

Low

Good Poor

Schizo. Risk

Communication

High Impairment

No Impairment No Impairment

LOWEST Impairment!

MedicalTreatment

•  AnLpsychoLc(NeurolepLc)MedicaLons–  Dopamineantagonistsareowenthefirstlineoftreatmentforschizophrenia

–  Beganinthe1950s– Mostmedica5onsreduceoreliminatetheposi5vesymptomsofschizophrenia

–  AcuteandpermanentextrapyramidalandParkinson‐likesideeffectsarecommon

–  Poorcompliancewithmedica5oniscommon

–  Risperdal,Olanzapineare“atypical”neurolep5cswithbeWerside‐effectprofilethan“Throrazine”

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PsychosocialTreatment

•  PsychosocialApproaches:OverviewandGoals–  Behavioral(i.e.,tokeneconomies)oninpa5entunits

–  Communitycareprograms

–  Socialandlivingskillstraining

–  Behavioralfamilytherapy

–  Voca5onalrehabilita5on

•  PsychosocialApproachesAreUsuallyaNecessaryPartofTreatment

Summary

•  SchizophreniaIncludesaSpectrumonCogniLve,EmoLonal,andBehavioralDysfuncLons

–  Posi5ve,nega5ve,anddisorganizedsymptomclusters

•  DSM‐IV‐TRDividesSchizophreniaIntoFiveSubtypes

•  OtherDSM‐IV‐TRDisordersIncludePsychoLcFeatures

•  GeneLc,Biological,andEnvironmentalCausaLveFactorsHaveBeenImplicatedforSchizophrenia

•  SuccessfulTreatmentRarelyIncludesCompleteRecovery