Pimavanserin is the first FDA-approved atypical antipsychotic drug indicated for 
the treatment of hallucinations and delusions associated with Parkinson's 
disease psychosis (PDP). Areas covered: This review focuses on the preclinical 
discovery of pimavanserin. It analyzes the pharmacological, behavioral and 
molecular mechanisms of pimavanserin and their contribution to the therapeutic 
advantages of the drug as reported in published preclinical and clinical 
studies, press releases and product labels. Expert opinion: Pimavanserin 
exhibits a unique pharmacological profile with nanomolar affinity at serotonin 
5-HT2A and 5-HT2C receptors. Functionally, it acts as a potent inverse agonist 
at 5-HT2A receptors, with selectivity over 5-HT2C receptors and no appreciable 
activity at other neurotransmitter receptors. Behavioral studies found that 
pimavanserin reversed impaired behaviors in animal models predictive of 
antipsychotic activity, and with no impairment of motor functions. The drug 
exhibits long plasma half-life (57 hours), which support its once/day 
administration. A pivotal phase III clinical trial demonstrated significant 
improvement in PDP symptoms in patients receiving pimavanserin compared to 
placebo-treated patients. The drug also displayed relatively benign safety and 
tolerability profiles. Pimavanserin's mechanism of action might contribute to 
its unique psychopharmacological properties in the improved treatment of PDP, 
and perhaps psychosis in other diseases including schizophrenia and 
dementia-related psychosis.