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The Dopamine Hypothesis

The Dopamine Hypothesis. Psychosis (schizophrenia?) is due to excessive dopaminergic tone Psychotic symptoms are relieved by blockade of dopamine receptors with neuroleptic medications. The Structure of Dopamine. The D2 Receptor. Distribution of Dopamine. Distribution of Dopamine Receptors.

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The Dopamine Hypothesis

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  1. The Dopamine Hypothesis • Psychosis (schizophrenia?) is due to excessive dopaminergic tone • Psychotic symptoms are relieved by blockade of dopamine receptors with neuroleptic medications

  2. The Structure of Dopamine

  3. The D2 Receptor

  4. Distribution of Dopamine

  5. Distribution of Dopamine Receptors

  6. Classical Neuroleptics • Phenothiazines (e.g., chlorpromazine, fluphenazine, thioridazine) • Butyrophenones (e.g., haloperidol) • Thioxanthenes (e.g., thiothixene) • Benzamindes (e.g., sulpiride)

  7. What Should We Call These Medications? • Neuroleptic • Antipsychotic • Antischizophrenic

  8. What Are the Target Symptoms? • Psychotic symptoms • Negative symptoms • Disorganized behavior and thinking • Cognitive impairments

  9. What is efficacy?Effect on positive symptoms, AND ... Positive Hallucinations Delusions Bizarre behavior Thought disorder Agitation Negative Flattened affect Anhedonia Avolition Social withdrawal Alogia Cognitive Learning Memory Attention Executive function Language skills Affective Depression Anxiety Aggression Dysphoria Psychomotoractivation

  10. Problems: Classical Neuroleptics • Incomplete efficacy: positive symptoms 10–20% non responders 50% residual symptoms • Minimal efficacy for other symptoms negative symptoms depressive symptoms cognitive dysfunctions

  11. Side Effects: Classical Neuroleptics • Parkinsonism (extrapyramidal side effects, or EPS) • Akathisia • Dystonia • Tardive dyskinesia

  12. Incidence of TD As a Function of Conventional Neuroleptic Exposure 50 40 30 20 10 0 Cumulative incidence of TD (% patients) (n=764) 0 1 2 3 4 5 6 7 8 9 10 Years of neuroleptic exposure Kane J. WWS, Davos, February 2000

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