• In ten of 30 schizophrenic patients treated with pimozide for five weeks, 20 mg of dextroamphetamine sulfate induced an increase in psychosis. The number of patients becoming more psychotic with the dextroamphetamine challenge was not significantly different from the number who worsened after dextroamphetamine challenge when pretreated with placebo. Half of the patients who showed a psychotic response to dextroamphetamine during placebo pretreatment responded to dextroamphetamine with an increase in psychosis after pimozide treatment. Dextroamphetamine induced a worsening in patients who had improved with pimozide. The stability of the preinfusion condition is more important to the type of response to dextroamphetamine than long-term pretreatment with a dopamine receptor blocker. The activation-euphoria response to dextroamphetamine was unaffected by pimozide pretreatment, which suggests that the changes in psychosis and activation may be regulated by different mechanisms. These findings question the postulated relationship between the antipsychotic drug response and dopamine receptor blockade.