Serotonergic and dopaminergic aspects of neuroleptic-induced extrapyramidal syndromes in nonhuman primates

Neuroleptic drug-induced acute extrapyramidal syndromes are one of the major reasons why patients discontinue their antipsychotic medicines. The typical (e.g., haloperidol) neuroleptic drug produces acute extrapyramidal symptoms in the majority of patients, whereas the atypical (clozapine) neuroleptic produces only minimal motor system side effects. Serotonin S₂ antagonists often reduce or prevent catalepsy in rodents, but the limited number of studies in nonhuman primates have produced conflicting results. The hypothesis of a high serotonin S₂/dopamine D₂ antagonism ratio as a mechanism underlying atypical neuroleptic effects in preventing acute extrapyramidal syndromes deserves further evaluation in nonhuman primate models because extrapyramidal symptoms in monkeys closely resemble those in patients. Cebus monkeys (22-28 years old) were tested with compounds that ranged from low to high S₂/D₂ antagonism ratios. These were haloperidol, fluphenazine, clopenthixol, melperone, tefludazine, setoperone, risperidone, and clozapine. A saline control was included with a wide dose range of each of these drugs that was tested in a once-weekly, blindly-scored random drug administration schedule. Dystonia was scored on four different symptoms by an experienced rater who was blind to drug dosage. All the compounds, with the exception of clozapine, produced clinically indistinguishable dose-related dystonia. The only difference was the dose at which dystonia appeared. In contrast to rodent studies, these nonhuman primate investigations with drugs, spanning a wide range of S₂/D₂ antagonism ratios, produced clinically similar extrapyramidal symptoms. Thus, adding an S₂ antagonism component to neuroleptics does not appear to provide an explanation for the motor side effect profile of atypical neuroleptics, or a method for designing neuroleptic drugs that will be free of extrapyramidal symptoms.