Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity

The combination of the noradrenergic agent atomoxetine plus the antimuscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different antimuscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different antimuscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology. Ten people with predominantly severe OSA completed a double-blind, randomized, placebo-controlled, cross-over trial. Participants completed three overnight in-laboratory sleep studies after either 80 mg atomoxetine + 5 mg solifenacin succinate (ato-sol) or 80 mg atomoxetine + 2 mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next-day subjective sleepiness [Karolinska Sleepiness Scale (KSS)], and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnea index versus placebo (P = 0.63). Ato-sol caused a shift toward milder respiratory events with reduced frequency of obstructive apneas (13 ± 14 vs. 22 ± 17 events/h; means ± SD, P = 0.04) and increased hypopneas during nonrapid eye movement (NREM) (38 ± 21 vs. 24 ± 18 events/h, P = 0.006) with improved nadir oxygenation versus placebo (83 ± 4 vs. 80 ± 8%, P = 0.03). Both combinations reduced loop gain by ∼10% versus placebo; sleep efficiency and arousal threshold were unaltered. Ato-bip reduced next-day sleepiness versus placebo (KSS = 4.3 ± 2.2 vs. 5.6 ± 1.6, P = 0.03). Atomoxetine + biperiden hydrochloride reduces perceived sleepiness, and atomoxetine + solifenacin modestly improves upper airway function in people with OSA but to a lesser extent versus recently published atomoxetine + oxybutynin (broad M-subtype receptor selectivity) findings. These results provide novel mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.NEW & NOTEWORTHY In contrast to recent findings of major reductions in OSA severity when atomoxetine is combined with a nonspecific antimuscarinic, oxybutynin (broad M-subtype receptor selectivity), addition of solifenacin succinate (M2 and M3 muscarinic receptor selectivity) or biperiden (M1 muscarinic receptor selectivity) with atomoxetine had modest effects on upper airway function during sleep, which provide mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.