Effects of the Combination of Pimavanserin and Atomoxetine on OSA Severity: A Randomized Crossover Trial

OSA pharmacologic interventions like the noradrenergic muscle stimulant atomoxetine have wake-promoting properties. Pimavanserin, a promising serotonin 2_A receptor antagonist, may help to counteract atomoxetine's noradrenergic effects by increasing arousal threshold and possibly reducing OSA severity.

What is the effect of the combination of pimavanserin and atomoxetine on apnea-hypopnea index (AHI; primary outcome), arousal index, and nadir oxygen saturation (Spo₂; secondary outcomes)?

After baseline polysomnography, 18 participants with OSA (AHI > 15 events/h) took pimavanserin plus atomoxetine (34/80 mg; 34/40 mg for the first 3 days) or placebo for 1 week according to a randomized, crossover, 2-period, double-masked clinical trial. Follow-up polysomnography was performed to provide study outcomes. Safety outcomes, subjective sleep quality, and flow-estimated endotypes (using oronasal pneumotachograph flow) also were explored.

Eleven and 7 participants were randomized to atomoxetine plus pimavanserin and placebo first, respectively. The combination reduced AHI by 42% (95% CI, 18%-60%) vs placebo, meeting the primary outcome (P < .001). Absolute AHI reduction was 16.9 events/h (95% CI, 8.1-23.6 events/h) more than placebo. Nadir Spo₂ and arousal index also were improved, by 5.0% (95% CI, 1%-8%) and 10.9 events/h (95% CI, 2.4-18.1 events/h) vs placebo. Overnight heart rate was increased (+4.8 beats/min; 95% CI, 1.5-8.1 beats/min), but no other change in subjective sleep quality or next-morning vital signs was evident. No increased risk for side effects was observed for the combination vs placebo. Treatment vs placebo improved pharyngeal collapsibility (+7.9% of stable breathing during sleep; 95% CI, 1.6%-14.1% of stable breathing during sleep), reduced loop gain by 20% (0.15; 95% CI, -0.23 to -0.07), and did not reduce the arousal threshold.

Our results indicate that pimavanserin with atomoxetine is a strong pharmacologic therapy candidate for OSA.

ClinicalTrials.gov; No.: NCT05350215; URL: www.

gov.