Pimavanserin for the treatment of Parkinson's disease psychosis

Introduction: Parkinson's disease (PD) is a neurobehavioral disorder defined by its motor features. Its treatment is frequently complicated by the presence of psychotic symptoms, most prominently hallucinations and delusions. These cause major distress and are the primary cause for nursing home placement. Current treatment requires either a reduction in medications for mobility or the addition of atypical antipsychotics, none of which are approved in the United States, and which are associated with major potential drawbacks. Areas covered: Information from extensive personal experience, a Pubmed literature search plus a direct request to Acadia Pharmaceuticals was used for this review. A brief review of the clinical problem and its current state of treatment will be followed by a discussion of pimavanserin and its potential role in treating PD psychosis (PDP). Several observations have implicated serotonin in the physiology of psychotic symptoms. Lysergic acid diethylamide, phencyclidine, and similar drugs that activate 5HT2A serotonin receptors produce psychotic syndromes, and almost all antipsychotic neuroleptics share the property of blocking the 5HT2A receptor as well as the dopamine D2 receptor. The reduced motor side effects of the second-generation antipsychotics have been ascribed to these drugs having greater 5HT2A antagonism than the first generation. Studies in animal models of psychosis have suggested benefits from drugs blocking the 5HT2A receptor alone without the motor side effects seen with D2 receptor antagonism. Expert opinion: Pimavanserin, a 5HT2A inverse agonist, has no motor side effects, and a remarkable safety profile that is comparable to placebo. Its antipsychotic effects coupled with its lack of motor side effects could make it an ideal drug for treating psychotic symptoms in PD, a major unmet need. One Phase III trial in PDP has demonstrated excellent tolerability and significant benefit. The FDA agreed to the filing of a planned new drug approval (NDA) for an indication in the treatment of PDP.