The combination of pimavanserin and atomoxetine reduces obstructive sleep apnea severity: a randomized crossover trial

BackgroundObstructive sleep apnea (OSA) pharmacological interventions like the noradrenergic muscle stimulant atomoxetine have wake-promoting properties. Pimavanserin, a promising serotonin 2A receptor antagonist, may help counteract atomoxetines noradrenergic effects by increasing arousal threshold and possibly reduce OSA severity. Research questionIn a randomized, crossover, two-period, double-blind clinical trial, we tested the effect of this drug combination on apnea-hypopnea index (AHI; primary outcome), arousal index and nadir oxygen saturation (SpO2; secondary outcomes). Study design and methodsFollowing baseline polysomnography, 18 OSA participants (AHI>15events/h) took pimavanserin-plus-atomoxetine (34/80mg; 34/40mg for the first 3 days) or placebo for one-week; follow-up polysomnography was performed to provide study outcomes. Safety outcomes, subjective sleep quality, and flow-estimated endotypes (using oronasal pneumotachograph flow) were also explored. ResultsEleven and seven 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<0.001). Absolute AHI reduction was 16.9 [8.1, 23.6] events/h greater than placebo. Nadir SpO2 and arousal index were also improved, by 5.0 [1, 8] % and 10.9 [2.4, 18.1] events/h vs. placebo. Overnight heart rate was increased (+4.8 [1.5, 8.1]), but no other change in subjective sleep quality or next-morning vital signs was evident. There was no increased risk for side effects on the combination vs. placebo. Treatment vs. placebo improved pharyngeal collapsibility (+7.9 [1.6, 14.1]%VEUPNEA), reduced loop gain by 20% (0.15 [-0.23, -0.07]), and did not reduce the arousal threshold. InterpretationPimavanserin with atomoxetine is a strong pharmacological therapy candidate for OSA.