Download - The Dopamine Hypothesis
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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