THE EVOLUTION OF THE SEROTONIN-DOPAMINE ANTAGONIST CONCEPT

Before the dopamine hypothesis of schizophrenia became established, a serotonin (5-hydroxytryptamine) 5-HT hypothesis was popular. This was based on the hallucinogenic properties of lysergic acid diethlyamide a nd abnormal serotonin levels in schizophrenics. Suggestions that serot onin might be involved in the cause of schizophrenia. or could be a ta rget for antipsychotic drug action began with the discovery that the a ntipsychotic agent clozapine is a potent serotonin 5-HT2A antagonist, as well as being a dopamine D-2 antagonist. This led to the formulatio n of the serotonin-dopamine antagonist (SDA) concept for antipsychotic s, with wider spectrums of activity and lower extrapyramidal side effe cts (EPS) liability. The principle of the SDAs is that the drug should be a potent serotonin 5-HT2A antagonist, with slightly less potent do pamine D-2 receptor-blocking properties. The clinical experience with risperidone, the first member of the new class of antipsychotics, seem s to offer the promise that the SDAs have significant advantages over both the conventional dopamine-blocking neuroleptics and the atypical antipsychotic clozapine. Risperidone has efficacy against both the pos itive and negative symptoms of schizophrenia and has a low tendency to produce EPS. Only time will tell whether other SDAs mill have the sam e advantages.