IS IT POSSIBLE TO PREDICT THE CLINICAL EFFECTS OF NEUROLEPTICS FROM ANIMAL DATA .5. FROM HALOPERIDOL AND PIPAMPERONE TO RISPERIDONE

In 1965 the first study of this series reported different effects of n euroleptics in rats, supporting clinical differences. At the one end, haloperidol presented as a potent and specific antagonist of the psych ostimulants amphetamine and apomorphine. Haloperidol-like neuroleptics have marked effects on psychomotor agitation, delusions and hallucina tions and bind with high affinity to dopamine-D2 receptors. Pipamperon e, at the other end, presented with weak ''dopamine'' antagonism and m ore striking tryptamine antagonism. Pipamperone is known to improve di sturbed sleep, social withdrawal and other symptoms of chronic schizop hrenia in the relative absence of extrapyramidal symptoms. These effec ts have been attributed to central serotonin-S2 antagonism, on the bas is of the clinical effects of ritanserin. As shown by the present anal ysis of relative tryptamine versus apomorphine antagonism of 57 neurol eptics, in comparison to relative S2 vs. D2 binding, there is a contin uity in the series. About 30 % of the compounds can be considered to a ct primarily as serotonin antagonists, but few are markedly more poten t than pipamperone. In amphetamine-challenged rats pipamperone-like ac tivity is reacted in preferential inhibition of the excessive oxygen c onsumption rather than of agitation. Risperidone inhibits oxygen consu mption (0.016 mg/kg) at the same dose as haloperidol inhibits agitatio n. Other low-dose effects of risperidone include reversal of amphetami ne-induced withdrawal, antagonism of agitation induced by a sequential tryptamine and apomorphine challenge and LSD-antagonism. In dogs, the antiemetic activity of risperidone is characterized by high oral effe ctiveness which lasts one day and agrees with pharmacokinetic data whe n allowance is made for the active metabolite 9-hydroxyrisperidone. In essence, risperidone has a pipamperone-like pharmacological profile, at low haloperidol-like doses and with virtually optimal pharmacokinet ics.