Abstract
Patients with Parkinson's disease almost uniformly experience sleep disorders. Sleep disorders have been linked to the severity of cognitive impairment, which is also a comorbidity with Parkinson's disease psychosis (PDP). Pimavanserin, a highly selective inverse agonist of the serotonin 2A receptor, is approved in the United States for the treatment of hallucinations and delusions in patients with PDP. Other atypical antipsychotics, such as quetiapine and clozapine, are frequently used off-label to treat PDP and have an increased risk of sedation and other sleep-related adverse events (eg, drowsiness, sedation). By contrast, a high degree of specificity for the serotonin 2A receptor may prevent pimavanserin from causing some of the off-target adverse events associated with other atypical antipsychotics. In this review and exploratory analysis, we summarize pimavanserin sleep- and sedation-related safety and tolerability data from past clinical trials, including 6 randomized controlled trials and 2 open-label extensions representing various pimavanserin doses (1 to 51 mg) in healthy volunteers, patients with PDP, and older patients with neurodegenerative disease. The results from our exploratory analyses suggest that pimavanserin may be associated with negligible levels of sedation and other sleep‑related adverse events and may provide improvements in nighttime sleep compared with placebo. Future head-to-head clinical trials will be needed for direct comparisons between pimavanserin and other atypical antipsychotics, such as quetiapine or clozapine.