DOPAMINE HYPOTHESIS FOR SCHIZOPHRENIA

MESOLIMBICSYSTEM MESOCORTICALSYSTEM
Pathway:VTAtolimbicsystem(nucleusaccumbens,ventralstriatum,amygdala,hippocampus) Pathway:VTAtocerebralcortex(PFC)DLPFCandVMPFC
Func>on:Responsibleforemo=onsandmemory Func>on:ResponsibleforaLen=on,planning,mo=vatedbehavior

UntreatedSchizophrenia: UntreatedSchizophrenia:
Posi=vesymptoms STRIATUM DLPFCresponsibleforcogni=vefunc=ons.
HYPERACTIVITY VMPFCresponsibleforaec=vesymtpoms. DLPFC
NAc HYPOACTIVITY

VTA VMPFC
VTA

TreatmentwithTypicalAn>psycho>c(D2Antagonist)
D2antagonistsinhibitDAfrombindinginthelimbicsystem.
Thisdecreasestheposi=vesymptoms.
HYPERACTIVITYtoNORMAL
TreatmentwithAtypicalAn>psycho>c(D2Antagonist,5HT2aAntagonist)
D2antagonistsinhibitDAfrombindinginthelimbicsystem.
Noeectof5HT2aantagonistsince5HT2areceptorsareabsentinthisregion.
NIGROSTRIATALSYSTEM
Pathway:Substan=anigratostriatum(caudateandputamen)
Func>on:Responsibleforneandpurposefulmotormovements(involvedinParkinson'sdisease)
TreatmentwithTypicalAn>psycho>c(D2Antagonist)
Produc=onofsecondarynega=vesymptoms.
Noworseningorimprovementofcogni=veandaec=vesx.
RemainLOW
TreatmentwithAtypicalAn>psycho>c(D2Antagonist,5HT2aAntagonist)
5HT2aantagonistss=mulatereleaseofDAbydisinhibi=ngGABAneurons
Improvescogni=ve,nega=veandaec=vesymptoms
withtheenhancedreleaseofDA
TUBEROINFUNDIBULARSYSTEM
Pathway:Arcuatenucleustomedianeminenceofhypothalamus
Func>on:Inhibitsprolac=nsecre=onfrompituitarygland

UntreatedSchizophrenia: UntreatedSchizophrenia:
NORMAL NORMAL

STRIATUM

Substan>aNigra ARCUATE MEDIAN

NUCLEUS EMINENCE

TreatmentwithTypicalAn>psycho>c(D2Antagonist) TreatmentwithTypicalAn>psycho>c(D2Antagonist)
BlockadeofD2receptorsinthenigrostriatalpathway,causesthereceptors DAnormallyinhibitsthereleaseofprolac=n
toupregulate.Thisupregula=onmayleadtotardivedyskinesia. D2antagonistspreventthereleaseofDA
NORMALtoLOW Increasedprolac=nrelease
NORMALtoLOW

TreatmentwithAtypicalAn>psycho>c(D2Antagonist,5HT2aAntagonist) TreatmentwithAtypicalAn>psycho>c(D2Antagonist,5HT2aAntagonist)
5HT2aantagonistss=mulatereleaseofDAbydisinhibi=ngGABAneurons 5HT2aantagonistss=mulatereleaseofDAbydisinhibi=ngGABAneurons
ForcessomeoftheD2antagonismtoberemoved,allowingforDArelease IncreasedlevelsofDAinhibitsthereleaseofprolac=n
ImprovesEPSsideeects Prolac=nlevelsreturntonormal
 SCHIZOPHRENIA
TMAPTreatmentAlgorithm STAGE1 SecondGenera8onAn8psycho8c
STAGE2 DierentSGA OR FirstGenera8onAn8psycho8c
STAGE3 Clozapine
STAGE4
STAGE5
Clozapine
FGAorSGA
+ FGA,SGAorECT

Notanagentthathasbeenpreviouslyused

STAGE6 FGA+SGA OR FGAorSGA+ECT OR FGAorSGA+otheragent

FIRSTGENERATIONANTIPSYCHOTICS
DosePotencyRelatedBlockedReceptorsPotencyRelatedSideEects ReceptorMediatedSideEects
Chlorpromazine(Thorazine) 100mg M1 ANTICHOLINERGIC MuscarinicReceptorBlockade
LOWPOTENCY

AutonomicNervousSystem
An=cholinergic
Thioridazine(Mellaril) 100mg H1 SEDATION
BBW:QTcProlonga=on
Drymouth,drowsiness,cons=pa=on,blurredvision
HistaminicReceptorBlockade
Mesoridazine(Seren>l) 50mg
BBW:QTcProlonga=on LOW 1 ORTHOSTATICHYPOTENSION Endocrine
Weightgain
Haloperidol(Haldol) 2mg D2 GenitourinarySystem
SEEDAHYPOTHESIS
Urinaryincon=nence
Sexualdysfunc=on
Fluphenazine(Prolixin) 2mg
AlphaAdrenergicReceptorBlockade
M1 EXTRAPYRAMIDALSIDEEFFECTS Cardiovascular
Thiothixene(Navane)
HIGHPOTENCY

4mg
Orthosta=chypotension
H1 NOSEDATION QTcProlonga=on
Triuperazine(Stelazine) 5mg
AbsenceofMuscarinicReceptorBlockade
Perphenazine(Trilaphon) 10mg HIGH 1 ORTHOSTATICHYPOTENSION CentralNervousSystem
ExtrapyramidalSideEects
D2 SEEDAHYPOTHESIS Dystonia
Loxapin(Loxitane) 10mg
Akathisia
Pseudoparkinsonism
Molindone(Moban) 10mg TardiveDyskinesia
Neurolep=cMalignantSyndrome
SECONDGENERATIONANTIPSYCHOTICS
(Listedinorderofincreasingecacy) TargetDoseLOW TxSpecicSideEectsTxSpecicAddi>onalInfo BlockedReceptorEects
CZP:Cardiometabolic Requires3motrialwithmaxbenetat1year
Clozapine(Clozaril)CZP 300mg Orthosta=chypotension MetabolizedbyCYP1A2(smoking)
5HT2A EXTRAPYRAMIDALSIDEEFFECTS
WEIGHTGAIN

Agranulocytosis Sialorrhea
OZP:Cardiometabolic Weightgainisdoserelated(uselowdose)
Olanazapine(Zyprexa)OZP 10mg An=cholinergiceects HYPERPROLACTINEMIA
2mg RSP:Hyperprolac=nemia Doses>6mghavenoincreasedbenet
Risperidone(Risperdal)RSP Movementdisorders>6mg NEGATIVESYMPTOMS
QTP:Seda=on QTP:Seda=on
Que>apine(Seroquel)QTP DAhasareciprocalrela=onshipwith5HT(ie5HT
400mg Cataracts Cataracts
DA).Byblocking5HT2Areceptors,youincreaseDA
WEIGHTNEUTRAL

inthemesocor=cal,nigrostriataland
APZ:Akathisia APZ:Akathisia tuberinfundibularpathwaysofthebrainand
Aripiprazole(Abilify)APZ 15mg
thereforedecreaseEPS,hyperprolac=nemiaand
nega=vesymptoms.Thereareno5HTreceptorsin
ZPR:QTcprolonga=on ZPR:QTcprolonga=on themesolimbicpathwaysoitisnoteected.
Ziprasidone(Geodon)ZPR 80mg
D2 SEEDAHYPOTHESIS
**LoweranityforD2receptorthanFGA