ANTIPSYCHOTIC PROFILE AND SIDE-EFFECT LIABILITY OF HALOPERIDOL, RISPERIDONE, AND OCAPERIDONE AS PREDICTED FROM THEIR DIFFERENTIAL INTERACTION WITH AMPHETAMINE IN RATS

Motor activity effects of haloperidol, risperidone, and ocaperidone were studied in rats challenged with amphetamine. At a low dose of amphetamine, the compounds were about equipotent in reducing amphetamine-induced hyperactivity to normal values (lowest ED50s: 0.01 5-0.023 mg/kg). Haloperidol completely blocked motility at a slightly higher dose (0.14 mg/kg). In contrast, much higher doses of risperidone and ocaperidone were required for complete blockade of motility (ED50s: 2.0 and 1.7 mg/kg, respectively). With increasing dose of amphetamine, risperidone became considerably less potent than haloperidol in reducing hyperactivity; ocaperidone remained at least as potent as haloperidol in this respect. Moreover, risperidone lost, while ocaperidone maintained, its high margin towards complete blockade of motility. The compounds were also equipotent (lowest ED50s: 0.0075-0.0089 mg/kg) in reversing amphetamine-induced behavioral withdrawal (stationary stereotypy) to more environment directed behavior (active exploration). However, this "disinhibitory" effect was maintained over a much wider dose range with risperidone than with haloperidol and ocaperidone. The observed differences in interaction with amphetamine are presumably related to relative serotonin 5HT2/dopamine D2 antagonistic activity and suggest important differences in therapeutic profile and side-eff ect liability of the compounds. The implications for distinct clinical applications of the compounds are discussed: risperidone might be the drug of choice for maintenance therapy of chronic schizophrenics, especially for patients with mild positive symptoms and type II patients with predominant negative symptoms and ocaperidone for therapeutic treatment of the pronounced positive symptoms in acute schizophrenia or during exacerbations of chronic schizophrenia.