USA: A single pimavanserin dose does not significantly impact arousal threshold or obstructive sleep apnea (OSA) severity, a recent study published in Annals of the American Thoracic Society has shown.
In a post hoc analysis, however, a subset of patients who displayed an increase in arousal threshold on pimavanserin showed a slight increase in the severity of OSA. "The desired effect on OSA severity might be achievable if the arousal threshold could be increased with pimavanserin, possibly with longer dosing to reach higher concentrations of the drug blood," the researchers wrote in their study.

A low respiratory arousal threshold is a critical endotype responsible for the pathogenesis of obstructive sleep apnea. In animal models, pimavanserin is an antiserotoninergic capable of CO2-mediated arousal suppression without affecting the respiratory motor response. It thus holds the potential for increasing the arousal threshold in OSA and subsequently reducing OSA severity.
Against the above background, Ludovico Messineo, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts, and colleagues measured the pimavanserin's effect on arousal threshold (primary outcome), arousal index, OSA severity, and other OSA endotypes (secondary outcomes) in a randomized, double-blind, crossover study.
For this purpose, the researchers included 18 participants with obstructive sleep apnea. The patients received a single dose of placebo or 34 mg pimavanserin 4 hours before in-lab polysomnography. Airflow measurement was done with an oronasal mask attached to a pneumotachograph, and the ventilatory drive was recorded with an intraesophageal electromyography catheter. Results are presented as mean or median changes (Δ).
The researchers reported the following findings:
Pimavanserin did not increase the arousal threshold nor decrease OSA severity or arousal index. It, however, prolonged total sleep time (Δ, 39.5 min).
In an exploratory analysis, a subgroup of seven patients who had a 10% or more increase in arousal threshold on pimavanserin exhibited a decrease in AHI4 (hypopneas associated with 4% desaturation) (Δ, 5.6 events/h) and hypoxic burden (Δ, 22.3 %min/h).
Although this is considered a negative study, it is possible that the pimavanserin dose was not optimized. It is also likely that the study needs to be more underpowered due to the extremely small sample size (18 participants). Increasing the sample size may also lead to more statistical significance after pimavanserin administration.
Reference:
Messineo L, Gell L, Calianese N, Sofer T, Vena D, Azarbarzin A, Labarca G, Taranto-Montemurro L, Yang HC, Wang TY, Kim M, Smith H, White D, Sands S, Wellman A. Effect of Pimavanserin on the Respiratory Arousal Threshold from Sleep: A Randomized Trial. Ann Am Thorac Soc. 2022 Dec;19(12):2062-2069. doi: 10.1513/AnnalsATS.202205-419OC. PMID: 35947827; PMCID: PMC9743476.