Multidose risperidone treatment evaluated in a rodent model of tardive dyskinesia

Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (<6 mg/day), but above this level is associated with parkinsonism and akathesia. The literature suggests an association between acute motor side effects and tardive dyskinesia (TD); therefore, we hypothesized that low dose levels of risperidone will spare TD. As clinical studies of TD liability with fixed doses of risperidone are difficult to conduct, we tested low and high doses of risperidone in a rodent model of TD, vacuous chewing movements (VCMs) production. Low doses of risperidone (1.5 mg/kg/day) resulted in control levels of VCMs after 6 months of treatment, whereas high doses of risperidone (6 mg/kg/day) produced VCM in the same range as haloperidol. Plasma drug levels are reported. If this animal model predicts TD risk in humans, the TD liability with low-dose risperidone is at a placebo level, whereas higher doses show haloperidol-like TD risk, as predicted from the acute motor effects.