Serotonergic aspects of acute extrapyramidal syndromes in nonhuman primates

Neuroleptic drug-induced acute extrapyramidal syndromes (EPS) are the major reasons why patients discontinue their antipsychotic medicines. Serotonin S2 antagonists prevent catalepsy in rodents but the effects in nonhuman primates have received only minimal study and deserve further evaluation as potential "non-neuroleptic neuroleptics" (antipsychotic effects free of acute EPS). Twenty Cebus monkeys (22 to 28 yrs. old) were tested with compounds that ranged from high to very low D2/S2 ratios. These were haloperidol, clopenthixol, tefludazine, and setoperone, all tested in the dosage range of .01 to .25 mg/kg and compared with saline i.m. once weekly in a random schedule. Dystonia was scored on four different symptoms by an experienced rater blind to drug dosage. All four active compounds produced clinically indistinguishable, dose related dystonia with very similar dose thresholds. In contrast to rodent studies these nonhuman primate investigations with drugs of widely differing D2/S2 antagonism ratios produced clinically similar EPS. Thus adding an S2 antagonism component to neuroleptics appears not to provide a unique approach to neuroleptic therapy which will be free of acute EPS.