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

2. WPA The Structure of Dopamine

3. WPA The D2 Receptor

4. WPA Distribution of Dopamine

5. WPA Distribution of Dopamine Receptors

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

7. WPA What Should We Call These Medications? NeurolepticNeuroleptic AntipsychoticAntipsychotic AntischizophrenicAntischizophrenic

8. WPA What Are the Target Symptoms? Psychotic symptomsPsychotic symptoms Negative symptomsNegative symptoms Disorganized behavior and thinkingDisorganized behavior and thinking Cognitive impairmentsCognitive impairments

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

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

11. WPA Side Effects: Classical Neuroleptics Parkinsonism (extrapyramidal side effects, or EPS)Parkinsonism (extrapyramidal side effects, or EPS) AkathisiaAkathisia DystoniaDystonia Tardive dyskinesiaTardive dyskinesia

12. WPA Incidence of TD As a Function of Conventional Neuroleptic Exposure 50 40 30 20 10 0 Cumulative incidence of TD (% patients) (n=764) 012345678910 Years of neuroleptic exposure Kane J. WWS, Davos, February 2000