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Pima at AD/PD 3-8-13http://www2.kenes.com/adpd/pages/home.aspx Evaluation of Therapeutic Ratios in Parkinson's Disease Psychosis: Comparison of Quetiapine, Clozapine and Pimavanserin K. McFarland, D.T. Hubbard, T. Howard, U. Hacksell ACADIA Pharmaceuticals Inc., San Diego, CA, USA Objectives: Psychosis is one of the major therapeutic challenges in Parkinson's disease (PD) and occurs in up to 40% of patients. Currently, there is no safe, tolerated, and effective treatment for Parkinson's disease psychosis (PDP) available but clozapine and quetiapine are often used off label. Since the dopamine antagonism of available antipsychotics blocks the activity of PD therapies, use of these drugs may lead to loss of motor control. These drugs also frequently cause undesirable sedation. An ideal PDP drug should have a therapeutic window which alleviates psychotic symptoms at doses that do not cause motor side effects. The present study determined effective doses for quetiapine, clozapine and the selective 5-HT2A antagonist pimavanserin in an animal model of PDP versus doses that caused sedation and DA blockade. Methods: Augmented amphetamine-induced locomotion in rats with bilateral substantia nigra (SN) lesions was used to assess antipsychotic efficacy in a PD model. Apomorphine-induced rotations in rats with unilateral 6-hydroxydopamine (6OHDA) lesions assessed anti-dopaminergic action, and reduction of spontaneous locomotion assessed sedation. Results: No dose of quetiapine and only a limited range of doses of clozapine were effective at reducing psychosis while maintaining motor function. In contrast, pimavanserin reduced psychotic symptoms at doses much lower than the doses reduced locomotion with no evidence of DA system disruption. Conclusions: These results suggest that effective treatment of PDP with quetiapine and clozapine has a significant risk of aggravating motor deficits. Pimavanserin, a selective 5-HT2A inverse agonist, may provide a safe, tolerated and effective therapy for PDP. Assigned speakers: Dr. Krista McFarland, ACADIA Pharmaceuticals Inc. , San Diego , USA Assigned in sessions: 08.03.2013, 09:00-17:00, Poster Session, POSTER02, POSTER SESSION 2, Poster Area |
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