Multidose Risperidone Treatment Evaluated in a Rodent Model of Tardive Dyskinesia

Abstract

Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (o6 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.

Neuroleptics and animal models: feasibility of oral treatment monitored by plasma levels and receptor occupancy assays

“…Previous studies in which plasma drug levels have been used as a drug efficacy monitoring parameter have shown high individual variability within groups of animals treated with the same dose of haloperidol or olanzapine in drinking water (see, i.e., plasma levels reported by Sakai et al 2001a, b;Gao et al 2005) supporting that this variability is not due to methodological issues. In addition, this variability has been shown not only in the case of animals treated through drinking water but also in the case of animals treated with mini-pumps, subcutaneous or intraperitoneal injections (see, i.e., Aravagiri et al 1999;Kapur et al 2003;Perrone et al 2004), supporting that this variability could be due to the fast clearance of these drugs and drug-derived metabolites from the bloodstream.…”

“…However, this later method could be difficult to use in large-scale experiments, as suggested by the study by Kapur et al (2003), and may be inappropriate for the delivery of some APDs like clozapine or quetiapine. Finally, the administration of drugs in drinking water has been also extensively used (see, i.e., Tamminga et al 1990;Kaneda et al 1992;Roberts et al 1995Roberts et al , 2002Gao et al 1997Gao et al , 2005Kelley et al 1997;Roberts 2001;Sakai et al 2001a, b;Roberts and Lapidus 2003;Kelley and Roberts 2004), whose major strengths include the avoidance of environmental stressors and the similarity of administration to the clinical situation. Although, in order to obtain an accurate measurement of the dose of the drug administered, close monitoring of water intake and other parameters such as plasma drug levels are necessary.…”

Differential Expression of Metabotropic Glutamate Receptors 2 and 3 in Schizophrenia: A Mechanism for Antipsychotic Drug Action?

“…To determine potential effects of chronic antipsychotic treatment on GCP II and mGluR3, Sprague Dawley rats (Charles River, Wilmington,MA) were treated with a first generation (haloperidol), second generation (risperidone) antipsychotic or placebo (n=10 each) in drinking water continuously for 6 months as previously described (14). Rats were then sacrificed, trunk blood collected and plasma frozen at −20°C until analysis.…”

Differential regional and dose-related effects of asenapine on dopamine receptor subtypes

“…Accordingly, the upregulation of striatal D 1 -like receptors after treatment with 0.3 mg/kg asenapine might offset the EPS associated with D 2 receptor upregulation in CPu and, subsequently, may contribute to a more benign neurological profile. It will be interesting to determine whether long-term administration of asenapine can induce vacuous chewing movements in rats, an adverse event commonly associated with repeated administration of typical antipsychotic drugs and is considered as an animal model of tardive dyskinesia (Gao et al 2006;Jeste et al 1998). …”