Schizophrenia

JimvanOs,ShitijKapur
Schizophreniaisstilloneofthemostmysteriousandcostliestmentaldisordersin
termsofhumansufferingandsocietalexpenditure.Here,wefocusonthekey
developmentsinbiology,epidemiology,andpharmacologyofschizophreniaand
provideasyndromalframeworkinwhichtheseaspectscanbeunderstoodtogether.
Symptomstypicallyemergeinadolescenceandearlyadulthood.Theincidenceof
thedisordervariesgreatlyacrossplacesandmigrantgroups,asdosymptoms,
course,andtreatmentresponseacrossindividuals.Geneticvulnerabilityissharedin
partwithbipolardisorderandrecentmoleculargeneticfindingsalsoindicatean
overlapwithdevelopmentaldisorderssuchasautism.Thediagnosisof
schizophreniaisassociatedwithdemonstrablealterationsinbrainstructureand
changesindopamineneurotransmission,thelatterbeingdirectlyrelatedto
hallucinationsanddelusions.Pharmacologicaltreatments,whichblockthe
dopaminesystem,areeffectivefordelusionsandhallucinationsbutlesssofor
disablingcognitiveandmotivationalimpairments.Specificvocationaland
psychologicalinterventions,incombinationwithantipsychoticmedicationina
contextofcommunitycasemanagement,canimprovefunctionaloutcomebutare
notwidelyavailable.100yearsafterbeingsonamed,researchisbeginningto
understandthebiologicalmechanismsunderlyingthesymptomsofschizophrenia
andthepsychosocialfactorsthatmoderatetheirexpression.Althoughcurrent
treatmentsprovidecontrolratherthancure,longtermhospitalisationisnot
requiredandprognosisisbetterthantraditionallyassumed.
Lancet2009;374:63545SeeCommentpage590
DepartmentofPsychiatryandPsychology,SouthLimburgMentalHealthResearchandTeachingNetwork,EURON,
MaastrichtUniversityMedicalCentre,Maastricht,Netherlands(ProfJvanOsPhD);andDivisionofPsychologicalMedicine,
InstituteofPsychiatry,KingsCollegeLondon,DeCrespignyPark,DenmarkHill,London,UK(ProfJvanOs,ProfSKapur
PhD)
Correspondenceto:ProfJimvanOs,DepartmentofPsychiatryandPsychology,MaastrichtUniversityMedicalCentre,POBox616,
6200MDMaastricht,[email protected]

Introduction
Althoughtheprecisesocietalburdenofschizophreniaisdifficulttoestimate,becauseof
thewidediversityofaccumulateddataandmethodsemployed,costofillnessindications
uniformlypointtodisquietinghumanandfinancialcosts.1Schizophreniadoesnotjust
affectmentalhealth;patientswithadiagnosisofschizophreniadie1215yearsbefore
theaveragepopulation,withthismortalitydifferenceincreasinginrecentdecades.2Thus,
schizophreniacausesmorelossoflivesthandomostcancersandphysicalillnesses.

Althoughsomedeathsaresuicides,themainreasonforincreasedmortalityisrelatedto
physicalcauses,resultingfromdecreasedaccesstomedicalcareandincreasedfrequency
ofroutineriskfactors(poordiet,littleexercise,obesity,andsmoking).2

Diagnosis
Identificationofdelusionsandhallucinationsinpsychosisisnotdifficult,buttheir
classificationhasnotbeensimple.Psychosisisnotexclusivetoschizophreniaandoccurs
invariousdiagnosticcategoriesofpsychoticdisorder(panel).Thecriteriausedto
distinguishbetweenthesedifferentcategoriesofpsychoticdisorderarebasedon
duration,dysfunction,associatedsubstanceuse,bizarrenessofdelusions,andpresenceof
depressionormania.However,theresultingdiagnosticcategoriesshowoverlapin
geneticliabilityamongthemselves3andwithbipolardisorder,46suggestingcommon
underlyingaetiology.
Analysisofthepsychopathologicalfeaturesinthevariouspsychoticdisorderssuggests
thatsymptomscanbeclusteredintofivemaincategories:(i)psychosis(encompassing
delusionsandhallucinationsalsocalledthepositivesymptomdimension);(ii)
alterationsindriveandvolition(lackofmotivation,reductioninspontaneousspeech,and
socialwithdrawalthenegativesymptom
dimension);(iii)alterationsinneurocognition(difficultiesinmemory,attention,and
executivefunctioningthecognitivesymptomdimension);and(ivandv)affective
dysregulationgivingrisetodepressiveandmanic(bipolar)symptoms.Thenegative
dimensionisassociatedwithneurocognitivealterations,butthepositiveandaffective
dimensionsofpsychopathologicalchangesarenot,7andthepositiveandnegative
symptomsseemtofollowindependentcoursesovertime.8
Withintheclusterofdiagnosticcategories,thetermschizophreniaisappliedtoa
syndromecharacterisedbylongduration,bizarredelusions,negativesymptoms,andfew
affectivesymptoms(nonaffectivepsychosis).Patientswhopresentwithapsychotic
disorderwithfewernegativesymptoms,butwhosepsychosisisprecededbyahighlevel
ofaffective(depressionandmania)symptoms,areusuallydiagnosedwithpsychotic
depressionorbipolardisorder(affectivepsychosis;figure1).
TheUSbased4thDiagnosticandStatisticalManualofMentalDisordersIV(DSMIV)
andthe10thInternationalClassificationofDiseases(ICD10)arecurrentlyusedto
diagnoseschizophrenia.However,thevariousworkgroupswhoaredevelopingthenext
generationofDSMandICD(DSMVandICD11;expectedafter2012)havetofind
solutionsforseveral

Seminar

Searchstrategyandselectioncriteria
WesearchedpublicationsinPubMedusingthesearchterms schizophr*[ti] or
psychosis[ti] or psychotic[ti] .Weused1558Englishlanguagereviewsandmeta
analysespublishedinthepast5years.ThesereportsweredownloadedintoanEndnote
libraryfileandscannedforrelevancewithregardtothetopicsselectedforthisreview.
FurtherfocusedsearchesonPubMedwerethendoneontheselectedtopics.
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635

Seminar
Panel:DSMIVmaindiagnosticcategoriesofpsychoticdisorders
Basedoncurrentprinciplesofdiagnosistakingintoaccountduration,dysfunction,
associatedsubstanceuse,bizarrenessofdelusions,copresenceofdepressionormania,
presenceofasomaticdisorder,andothercriteria.

Nonaffectivepsychoticdisorders:

Schizophrenia

Schizoaffectivedisorder

Schizophreniformdisorder

Delusionaldisorder

Briefpsychoticdisorder

Psychoticdisordernototherwisespecified

Affectivepsychoses:

Bipolardisorderwithpsychoticfeatures

Majordepressivedisorderwithpsychoticfeatures

Substanceinducedpsychoticdisorder:AlcoholinducedOthersubstanceinduced

Psychoticdisorderduetoageneralmedicalcondition
636
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difficultdiagnosticissues.First,howmanydisordersoughttobecarvedoutofthecurrent
clusterofcategories(panel)?Andhowshouldaspecificcategoryofschizophreniabe
definedamongthem?Second,doesdiagnosisofschizophreniarefertoacategorical
illness(suchasHuntingtonsdiseasethatoneeitherhasorhasnot)orisitacontinuous
ordimensionalconcept(suchastheregularlyreviewedboundariesofarterialblood
pressureabovewhichhypertensionisdiagnosed)?Finally,isthe19thcenturyexpression
referringtoastateofsocalledsplitmindasuitabletermtodiagnosepatientsinthe21st
century?
Thecurrentdiagnoses(panel)areunlikelytorepresentdiscretenosologicalentities.9For
example,schizophrenialikepsychopathologicalchangesarealsoexpressed,inan
attenuatedform,inindividualswithschizotypalorschizoidpersonalitytraits.A
systematicreviewofgeneralpopulationsurveysindicatedthattheexperiencesassociated
withschizophreniaandrelatedcategoriessuchasparanoiddelusionalthinkingand
auditoryhallucinationsareobservedinanattenuatedformin58%ofhealthypeople.10
Theseattenuatedexpressionscouldberegardedasthebehaviouralmarkerofthe
underlyingliabilityforschizophreniaandrelateddisorders,justashighbloodpressure
indicateshighsusceptibilityforcardiovasculardiseaseinadoseresponsefashion.
Becauseofevidenceforsharedgeneticcausesunderlyingdiagnosesofpsychotic
disorders,includingbipolardisorder,andevidenceforcontinuitywithmentalactivityin
healthyindividuals,amajorprobablechangeinDSMVandICD11istheadditionof
dimensionalindicatorsthatcanbeappliedacrossdiagnosticcategoriesofaffectiveand
nonaffectivepsychoticdisorder(figure2).
Researchsuggeststhattheuseofacombinationofdimensionalandcategorical
representationsofpsychopathologyforthepurposeofdiagnosisinpsychoticdisorders
conveysmoreinformationabouttreatmentneedsandprognosis.11
Adebateexistsastowhetherthetermschizophrenia,whichreferstoastateofsocalled
splitmind,shouldberetainedinDSMVandICD11.1215Japanwasthefirstcountryto
abandonthetermschizophrenia,andmodifiedthenameoftheillnessfromSeishin
BunretsuByo(mindsplitdisease)intoTogoShitchoSho(integrationdysregulation
syndrome).Thechangeofnamehadaninstantresponse.Mostpsychiatristsstartedusing
itinthefirstyear,bringingaboutanimprovedcommunicationofdiagnosistopatients
andbetterperceptionofthedisorder.16Thus,thetermschizophreniawillcontinueto
evolve;however,theunderlyingmechanismsandtheeffectonthepersonwillnot
change.

Epidemiology
Asystematicreviewofepidemiologicaldataindicatesthat,ifthediagnosticcategoryof
schizophreniaisconsideredinisolation,thelifetimeprevalenceandincidenceare
030066%and102220per100000personyears,respectively.17Ratesvarythreefold
dependingonthediagnosticdefinitionofschizophreniathatisused:anarrowdefinition,

includingpatientswithillnessdurationofatleast6months,agebelow45years,and
negativesymptomshaslowerratesthanabroaddefinitionwithlessspecificcriteria.18A
recentlandmarkstudyallowingforabroaddefinitionofpsychoticdisorder,including
diagnosticcategoriessuchasdelusionaldisorder,briefpsychoticdisorder,andthecatch
alldiagnosticcategoryofpsychoticdisordernototherwisespecifiedrevealedalifetime
rateofschizophreniaandrelatedcategoriesof23%,19risingto35%ifotherpsychotic
disorders,suchasbipolardisorderandsubstanceinducedpsychoticdisorder,were
included.
Diagnosticcategoriesthatarebiasedtowardsnegativesymptomsandlongdurationof
illness(bothassociatedwithpooroutcome)producediagnosticcategorieswithhigher
incidenceratesformenthanforwomen,20whereasthoseincludingmoreaffective
symptomsandbriefpresentations(associatedwithbetteroutcome)showsimilarratesin
menandwomen.18,21Thesedatasuggestthatthesymptomaticexpressionofschizophrenia
andrelateddiagnosesismoresevereinmenthaninwomen.Thefindingofanearlier
onsetinmenthaninwomensupportsthisnotion.17,18

Perinatalandearlychildhoodfactors
Prospectivestudieshaveshownthatsomefactorsinfetallifeincludinghypoxia,
maternalinfection,maternalstress,andmaternalmalnutritionmightaccountforasmall
proportionofincidenceofschizophrenia.2225Birth
cohortandhighriskstudieshaveyieldedconsistentevidencethat,asagroup,children
whoasadultswillbediagnosedwithschizophreniahave,comparedwiththeirpeers,a
higherincidenceofnonspecificemotionalandbehaviouraldisturbancesand
psychopathologicalchanges,intellectualandlanguagealterations,andsubtlemotor
delays.2628Someofthesedevelopmentalindicatorscouldberelevantfordifferential
diagnosiswithintheclusterofdiagnosticcategoriesbecausemotorandcognitive
alterationsseemtobespecificforthediagnosisofschizophrenia(ie,havenotbeen
observedinbipolardisorder).2931

Environmentalfactors
Systematicreviewsofepidemiologicalstudieshaveindicatedthattherateof
schizophreniaandrelateddisordersisaffectedbysomeenvironmentalfactors.17,32First,
theriskofschizophreniaandrelatedcategoriesincreaseslinearlywiththeextenttowhich
theenvironmentinwhichchildrengrowupisurbanised(oddsratio[OR]~2).33Second,
evidenceexiststhatsomeimmigrantethnicgroupshaveahigherriskofdeveloping
psychoticdisordersthanhavenativebornindividuals,34particularlyiftheyliveinalow
ethnicdensityarea,oranareawheretherearefewerpeopleofthesamemigrantgroup
(OR25).35,36Third,randomisedexperimentalstudieshaveshownthatexposureto
dronabinol,themainpsychotropiccomponentofcannabis,causesmildandtransient
psychoticstates37,38towhichindividualswithpreexistingliabilitytopsychosisaremore
susceptiblethanarehealthycontrols.39,40

Systematicreviewsofprospectivestudieshavesuggestedthatcannabisuseisassociated
withincreasedriskforpsychoticdisorderandsymptoms(OR1520).41Although
establishmentofcausalityonthebasisofepidemiologicaldataisdifficult,42theacute
psychoticstatesinducedbydronabinolprovideanimportantmodelofpsychotic
symptoms,especiallyasnationalregisterfollowupstudieshavesuggestedthatcannabis
inducedacutepsychoticstatestreatedinpsychiatricservicesaretheearlysignsof
schizophreniaandrelateddisorders.43,44
Thelargeeffectsizes,intermsofrelativerisk(5)andhighfraction(30%)ofoverall
incidenceattributabletoenvironmentalfactorsinurbanisedareas,migrantandethnic
group,andcannabis,assumingcausality,raiseanumberofimportantissues.First,the
associationwithurbanisationandmigrationmightindicateacommonenvironmental
influencelinkedtochronicexperienceofsocialdisadvantageandisolation,45suggesting
thatpublichealthpoliciestargetingthesefactorsmightalsoaffectratesofschizophrenia.
Furtherworkisneededfocusingontheidentificationofspecificenvironmental
influencesandmechanismsunderlyingtheproxyriskfactorsofmigrationandextentof
urbanisation.Somestudiesareattemptingthisaimusingvirtualreality46ormomentary
assessmentdesigns.47
Figure1:Principlesunderlyingthemaindistinctionbetweenaffectivepsychosis(eg,bipolardisorderand
psychoticdepression)andnonaffectivepsychosis(eg,schizophreniaandschizophreniformdisorder)

Seminar
Moreacuteonset,betteroutcome
Moreinsidiousonset,pooreroutcome

Psychosis:delusions,hallucinations

ManiaNegativesymptoms
DepressionCognitiveimpairment

Affectivedysregulation

Developmentalimpairment

Schizophrenia
Mania
Negativesymptoms
Mania
Negativesymptoms
Cognitiveimpairment
Depression
Cognitiveimpairment
Mania
Depression
Psychosis
Psychosis

Depression

Negativesymptoms
Cognitiveimpairment
Psychosis
Bipolardisorder

Schizoaffectivedisorder
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Figure2:Threehypotheticaltypicalpatientsdiagnosedwithacombinationofcategoricalanddimensional
representationsofpsychopathologyCategoricaldiagnosesofschizophrenia(blue),bipolardisorder(green),and
schizoaffectivedisorder(violet)areaccompaniedbyapatientsquantitativescores(connectedbyredlines)onfive
maindimensionsofpsychopathology.

Second,sincetheincidenceandexpressionofschizophreniavariesindifferentsocial
contexts,alevelofexplanationfocusingontheeffectoftheenvironmentoncognitive
schemataaswellasonbrainneurobiologicalmechanismsisnecessary.Forexample,
exposuretotraumaduringchildhoodcouldpredisposetoaparanoidwayofthinking48,49
and,whenthisispairedwithasensitiseddopaminesystem,50itcouldpredisposethe
individualtopsychoticdisorder.

Seminar

181716151413121110
987654321

0%50%Goodoutcome
100%
Pooroutcome

Figure3:OutcomeheterogeneityinschizophreniaSummaryof18prospectivelydesignedoutcomestudiesoffirst
admissionandfirstdiagnosisofschizophreniawithfollowupofmorethan1yearwithvariablydefinedgoodandpoor
outcomes,showingbalancedproportionsofgoodandpooroutcomesacrossstudies.Studies1to18arereferences76
93.Examplesofgoodoutcomes:symptomaticrecoverywithnosocialorintellectualdeficitthroughoutfollowup
(study2,reference77);fullrecoveryoverfollowup(study12,reference87);completeremissionandneverreadmitted
(study16,reference91).Examplesofpooroutcomedefinition:severechronicsocialorintellectualdeficit(study2,
reference77);moderatetoseveresymptomsattimeoffollowup(study12,reference87);chroniccontinuous
psychoticsymptomsoverfullfollowuptime(study16,reference91).Forfulldescriptionofalloutcomedefinitions

seereference94.

Third,althoughmigrationandcannabisusedonotseemtobespecificforaparticular
diagnosticcategoryamongthedifferentpsychoticdisorders,urbanisationexposureis
associatedwiththediagnosticcategoryofschizophreniaandnotwithbipolardisorder,51
suggestingthatsomeenvironmentalexposuresaffectdifferentcausalpathwaysresulting
inspecificpsychopathologicaloutcomes.
Finally,thefactthatonlyaminorityofthoseexposedtourbanenvironments,migration,
andcannabisdevelopschizophreniaindicatesthatsomeareresilienttotheseriskfactors.
Thebasisforthisresiliencecouldhelpdevisepublichealthstrategies.

Geneandenvironmentinterplay
Vulnerabilityforschizophreniaispartlygenetic.Twinstudiessuggestthatthesyndrome
hasheritabilityestimatesofaround80%(comparedwith~60%forosteoarthritisofthe
hipand3050%forhypertension).Despitethisgeneticassociation,theidentificationof
specificmoleculargeneticvariationhasnotbeeneasy.Modificationofdiagnosticcriteria
anduncertaintyaboutthenaturalphenotypeofpsychosisarelikelytohavehampered
progressinthisregard.
Recentfindingshavesuggestedthatasmallproportionofschizophreniaincidencecouldbe
explainedbyrare
structuralvariations(copynumbervariantsoccasionedbysmallduplicationsordeletions,
orinversions).Thesegenomicvariantsareusuallyrareindividually,buthavenowbeen
observedatahigherrateinautism52andschizophreniacomparedwithcontrols,5358
suggestingapossiblesharedneurodevelopmentalpathwayforthesedisorders.59Similarly,
newgenomewideassociationstudieshaveyieldedthefirstgenomewideresultsrepli
catedacrossmultiplesamplesforbipolardisorderandschizophreniaontheonehand,and
evidencesuggestiveforassociationacrossdisordersontheotherhand.60,61
Thehighheritability(80%)ofschizophreniaisnotonlyduetogeneticinfluencesbutalso
duetoenvironmentaleffectsthataremoderatedbygenes(geneenvironment
interaction).Epigeneticfactorssusceptibletoenvironmentalinfluencemightalsoaffect
twinheritabilityestimates.62Metaanalyticworksuggeststhatpaternalageabove40years
isassociatedwithschizophrenia,indicatingthatepigeneticmechanismsmighthavea
role.63Geneticepidemiologicalstudieshaveproposedthatgeneenvironmentinteraction
inschizophreniaandrelateddiagnosticcategoriesiscommon.64Therefore,theworldwide
challengeistobringtogetherthevariousdisciplinesthatareneededtoexaminemodels
ofdiseasecausationbasedonvariousaspectsofgeneenvironmentinterplay.65
Researchintwinsandfirstdegreerelativesofpatientshasshownthatthegenes
predisposingtoschizophreniaandrelateddisordersaffectsomeheritabletraits6668that
underlietheillness:neurocognitivefunctioning,structuralMRIbrainvolumemeasures,

neurophysiologicalinformationprocessingtraitsandsensitivitytostress.6972Theseso
calledintermediaryphenotypes(becausetheyarebetweenthepredisposinggenesandthe
diseasephenotype)mightbeclosertoalterationsingenefunctionthanthediagnostic
categoryofschizophreniaandrelateddisorders,andforthisreasoncouldbeuseful
targetsformoleculargeneticstudies.Someoftheseintermediaryphenotypescouldbe
diagnosticallyrelevant;forexample,theintermediaryphenotypeofcognitiveimpairment
couldhavehighspecificityforthediagnosticcategoryofschizophrenia.Indeed,meta
analyticworkhasindicatedthatrelativesofpatientswithbipolardisorderhaveonly
minimalcognitivealterations.73

Prognosis
Thetraditionalclinicalandsocietalviewofschizophreniaisofadebilitatingand
deterioratingdisorderwithpooroutcome.However,mostpatientsnowlive
independentlyoutsidethehospitalandthetypicaldurationofadmissionisshort(afew
weeks).Althoughmostpatientsneedsomedegreeofformalorinformalfinancialand
dailylivingsupport,theperspectivenowisoneofrecovery,wherethepatienttakesan
activeroleinthedevelopmentofnewmeaningandpurposewhilegrowingbeyondthe
misfortuneofmentalillness.74,75
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Seminar
Prospectivelydesignedoutcomestudiesoffirstadmissionandfirstdiagnosisof
schizophreniawithfollowuptimeofmorethan1yearhavesuggestedthatheterogeneity
iscommonwithpooroutcomeinlessthan50%ofpatientsand,similarly,withgood
outcomeinlessthan50%ofpatients(figure3).Therefore,thecourseandoutcomeof
schizophreniaischaracterisedbymainlyunexplained94heterogeneityratherthanuniform
pooroutcome.95Understandingofthesedataandcommunicationtopatientsandtheir
familiesatthetimeofdiagnosisarecrucialsteps,becausepatientsandfamiliesoften
sufferforthecommonassumptionofanegativeoutcome.

Pathophysiology
Sincetheadventofmodernneuroimagingtechniques,thenumberofstudiesofthe
pathophysiologicalchangesofschizophreniahasdramaticallyincreased,withmorethan
1000reportspublishedinthepast10years.Structuralbrainimagingstudieshaveshown
asubtle,almostuniversal,decreaseingreymatter,enlargementofventricles,andfocal
alterationofwhitemattertracts.9698
Neurochemicalimagingstudiestotestthedopaminehypothesisofschizophreniawith18F

dopaand11Cracloprideareconsistentinshowingthatschizophrenia,initsacute
psychoticstate,isassociatedwithanincreaseindopaminesynthesis,dopaminerelease,
andrestingstatesynapticdopamineconcentrations.99,100Theseneurochemicalfindings
providealogicallinktothefactthatallcurrentpharmacologicaltreatmentsof
schizophreniablockdopaminereceptors.101Abnormalbrainstructureandneurochemical
compositionleadtoabnormalfunctionthatisshownbyfunctionalMRI(fMRI)and
electrophysiologicaltechniques.fMRIstudiesshowabnormalitiesinthebrainresponse
tocognitivetasks,withanabnormalnetworkresponsecharacterisedbyboth
hyperactivityandhypoactivityindifferentbrainregions(comparedwiththeresponsein
healthyvolunteers),dependingonthespecifictasks.102Eventrelatedpotentialstudies
havelookedattheresponseofpatientstonovelstimuli(P300)andtorepeatedstimuli
(P50),showingthatpatientshaveadiminishedbrainresponsetonewstimulianda
decreasedabilitytosuppressbrainactivationinresponsetorepeatedstimuli.70,103In
conclusion,diagnosisofschizophreniaisassociatedwithalteredbrainfunction;however,
theseresultsraisethequestionofwhyachangeindopamineconcentrationsleadsa
persontobecomeconvincedthattheircolleaguesareconspiringandthepoliceareoutto
getthem.
Severalrecenttheoriesattempttofillthegapbetweenbiologicalalterationsandactual
experiencesreportedbypatients.104,105Onesuchtheoryisbasedonthefactthatneuronsin
thedopaminesystemfireinresponsetonovelrewardsintheenvironment,andthatthe
releaseddopamineleadstoaswitchinattentionandbehaviour
towardstherewardingsituation,thusimbuingthestimuluswithmotivational
salience.106,107Aberrantfiringofthedopaminesystemmightleadtotheaberrant
assignmentofmotivationalsaliencetoobjects,people,andactions.105,108,109Thepatient
thenmakesanefforttointerprettheseaberrantexperiencesandconstructsaseemingly
plausible(tothem)accounttounderstandthechangingsituation.
Thus,amixtureofdopaminedysregulationandaberrantassignmentofsalienceto
stimuli,togetherwithacognitiveschemethatattemptstograpplewiththeseexperiences
togivethemmeaning,mightleadtothedevelopmentofpsychoticsymptoms.110
Alterationsinaffectivestate(depressionormania)andsomewaysofthinking,suchasa
tendencytojumptoconclusions,mightcombinewiththedopaminedysfunctionto
increasetheriskofdelusionformation.111

Clinicalmanagement
DiagnosisofschizophreniaismadebyreferencetothecriteriainDSMIVandICD10.
Eventhoughtheseareclinicalcriteria,diagnosiscanbeachievedwithacceptablyhigh
interraterreliabilityandcompareswellwithdiagnosticreliabilityintherestofmedicine.
Unfortunately,noobjectivetestexistsforthisdiagnosis.Althoughseveralbiological
abnormalitieshavebeenreproduced(eg,abnormallylargeventricles,abnormaldopamine
concentration,andalteredP300),theyarenotsensitiveenough(usuallyseenonlyin40
50%ofpatients)ornotspecificenough(seenin30%offirstdegreerelativesand10%of

otherwisenormalcontrols)tobeofdiagnosticusefulness.112Thus,diagnosisisbasedon
confirmationofthekeysymptomsandeliminationofthemostprobabledifferentials
(drugabuse,contributoryneurologicalconditions,ormetabolicillness).
Oncethediagnosisismade,antipsychoticdrugs,whichblockdopamineD2receptors,113
arethemaintreatmentofschizophrenia.Firstgenerationagentsdiscoveredinthe
1950s,alsocalledfirstgenerationantipsychotics(eg,haloperidolandchlorpromazine)
areeffectiveinthetreatmentofpsychoticsymptoms,butoftenleadtomotorsideeffects.
Inthepast10years,newagents,knownasthesecondgenerationantipsychotics
risperidone,olanzapine,quetiapine,ziprasidone,andaripiprazolethatlessfrequently
causemotorsideeffectshavebeenintroducedfortreatment.Initially,therewasoptimism
thattheywouldimprovenotonlythepositivepsychoticsymptomsbutalsothenegative
andcognitiveaspectsofthesyndrome.Althoughthenewsecondgenerationanti
psychoticdrugsareeffectiveintreatingpositivesymptomswithareducedburdenof
motorsideeffects,thepromiseofefficacyagainstnegativeandcognitivesymptomshas
notbeenborneout.114,115Additionally,thenewantipsychoticstendtoinduceahigh
incidenceofmetabolicsideeffects(weightgain,increasedtriglyceridesand
cholesterol).
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Affectivegeneticrisk