WPAWPA

The Dopamine HypothesisThe Dopamine Hypothesis

• Psychosis (schizophrenia?) Psychosis (schizophrenia?) is due to excessive is due to excessive dopaminergic tonedopaminergic tone

• Psychotic symptoms are Psychotic symptoms are relieved by blockade of relieved by blockade of dopamine receptors with dopamine receptors with neuroleptic medicationsneuroleptic medications

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The Structure of The Structure of DopamineDopamine

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The D2 ReceptorThe D2 Receptor

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Distribution of DopamineDistribution of Dopamine

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Distribution of Dopamine Distribution of Dopamine ReceptorsReceptors

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Classical NeurolepticsClassical Neuroleptics• PhenothiazinesPhenothiazines (e.g., chlorpromazine, (e.g., chlorpromazine,

fluphenazine, thioridazine)fluphenazine, thioridazine)• Butyrophenones (e.g., Butyrophenones (e.g.,

haloperidol)haloperidol)• Thioxanthenes (e.g., thiothixene)Thioxanthenes (e.g., thiothixene)• Benzamindes (e.g., sulpiride)Benzamindes (e.g., sulpiride)

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What Should We What Should We Call These Call These

Medications?Medications?

• NeurolepticNeuroleptic

• AntipsychoticAntipsychotic

• AntischizophrenicAntischizophrenic

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What Are the Target What Are the Target Symptoms?Symptoms?

• Psychotic symptomsPsychotic symptoms

• Negative symptomsNegative symptoms

• Disorganized behavior and Disorganized behavior and thinkingthinking

• Cognitive impairmentsCognitive impairments

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What is efficacy?What is efficacy?Effect on positive symptoms, AND ...Effect on positive symptoms, AND ...

Affective

Depression

Anxiety

Aggression

Dysphoria

Psychomotoractivation

Cognitive

Learning

Memory

Attention

Executive function

Language skills

Negative

Flattened affect

Anhedonia

Avolition

Social withdrawal

Alogia

Positive

Hallucinations

Delusions

Bizarre behavior

Thought disorder

Agitation

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Problems: Classical Neuroleptics Problems: Classical Neuroleptics

• Incomplete efficacy: positive symptomsIncomplete efficacy: positive symptoms10–20% non responders10–20% non responders

50% residual symptoms

• Minimal efficacy for other symptoms Minimal efficacy for other symptoms negative symptomsdepressive symptomscognitive dysfunctions

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Side Effects: Classical Side Effects: Classical NeurolepticsNeuroleptics

• Parkinsonism Parkinsonism (extrapyramidal side effects, (extrapyramidal side effects, or EPS)or EPS)

• AkathisiaAkathisia

• DystoniaDystonia

• Tardive dyskinesiaTardive dyskinesia

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Incidence of TD As a Function of Incidence of TD As a Function of Conventional Neuroleptic ExposureConventional Neuroleptic Exposure

50

40

30

20

10

0

Cu

mu

lati

ve i

nci

den

ce o

f T

D

(% p

atie

nts

) (n

=76

4)

0 1 2 3 4 5 6 7 8 9 10

Years of neuroleptic exposureKane J. WWS, Davos, February 2000