[Serotonin antagonism involved in the antipsychotic effect. Confirmation with ritanserine and risperidone]

Shortly after the introduction of the first neuroleptics a serotonin hypothesis of schizophrenia has been proposed. But neuroleptics in animals and in man were found to produce effects more consistently related to inhibition of the dopaminergic than of any other type of neurotransmission. However, two early neuroleptics, pipamperone and clozapine, act pharmacologically more on 5-HT2 than on D2 receptors. Both have a distinct clinical profile and low EPS liability. The development of selective 5-HT2-antagonists, devoid of LSD-like properties, resulted in a first compound, ritanserin. Clinically, the highly specific 5-HT2-antagonism of ritanserin improves dysthymia, increases slow wave sleep and supports classical neuroleptic treatment by decreasing negative symptoms and EPS. These properties, being valuable by themselves, have been associated to dopamine D2-antagonism in the new antipsychotic risperidone, which is an extremely potent 5-HT2-antagonist. At doses of 5 mg daily risperidone acts on both negative and positive symptoms of schizophrenia in the virtual absence of EPS.