The role of serotonin in schizophrenia and the place of serotonin-dopamine antagonist antipsychotics

After four decades of the use of antipsychotic drugs that target the dopamine D₂ receptor as the initial site of action, a new strategy for antipsychotic therapy has emerged and, with it, new hope for greater efficacy and fewer side effects. This new strategy involves identifying drugs with strong serotonin (5-hydroxytryptamine) 5-HT_2A receptor relative to dopamine D₂ receptor blocking properties. Clozapine is now known to have these properties, but risperidone is the first drug to be designed intentionally to have these properties. Others are being developed. These drugs, the serotonin-dopamine antagonists (SDAs), may prove to have many other uses in psychiatry beyond schizophrenia because of their low propensity to cause extrapyramidal symptoms. Their pharmacologic mechanism of action may be more complex than only strong 5-HT_2A and weak D₂ block, e.g., 5-HT_2C and D₄ receptor blockade. Nevertheless, the SDAs are proving to be valuable tools in the analysis of both normal brain function and the etiology of schizophrenia.