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

WPA The Structure of Dopamine

WPA The D2 Receptor

WPA Distribution of Dopamine

WPA Distribution of Dopamine Receptors

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)

WPA What Should We Call These Medications? NeurolepticNeuroleptic AntipsychoticAntipsychotic AntischizophrenicAntischizophrenic

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

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

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

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

WPA Incidence of TD As a Function of Conventional Neuroleptic Exposure Cumulative incidence of TD (% patients) (n=764) Years of neuroleptic exposure Kane J. WWS, Davos, February 2000