The predictive validity of
catalepsy as a rodent model for detecting the extrapyramidal side effects (EPS) of
antipsychotic drugs was recently questioned when the novel
antipsychotic savoxepine produced little
catalepsy in rodents while producing significant EPS in schizophrenic patients. Because
catalepsy is viewed as an important model for predicting EPS, we decided to re-evaluate the effects of
savoxepine.
Savoxepine,
clozapine,
haloperidol,
olanzapine,
ORG 5222,
raclopride, and
risperidone were examined in two tests for
catalepsy (grid and bar tests) in male Sprague-Dawley rats. The ability to antagonize
amphetamine-induced hypermotility was also examined, since this measure is believed to predict clinical efficacy. With the exception of
clozapine, all drugs produced dose-dependent
catalepsy in both tests. For each
drug, the minimum effective dose for producing
catalepsy was greater than or equal to the ED50 for antagonizing
amphetamine-induced hyperactivity (defined as the dose producing a 50% reduction in hyperactivity).
Clozapine resulted in the widest separation of effective doses in the
catalepsy and activity models.
Raclopride produced the next largest separation while the remaining drugs resulted in only a one- or two-fold dose separation between the two behavioral tests. The results with
haloperidol and
clozapine are consistent with the clinical effects of these drugs (severe versus mild EPS). The ratios of effective doses in
catalepsy and activity for the remaining novel drugs are also consistent with preliminary clinical findings indicating some EPS with each of these compounds. Thus,
catalepsy remains a suitable rodent model for detecting compounds with EPS liability in humans.