Atomoxetine Combo for Sleep Apnea

Combining an ADHD med with an antimuscarinic improved sleep apnea in this phase III trial

STUDY: Strollo PJ Jr et al, Am J Respir Crit Care Med 2026;00:1–15

STUDY TYPE: Randomized controlled trial

FUNDING: Apnimed, Inc.

Background

Sleep apnea causes many psychiatric disorders. 1 in 4 Americans have it, but nearly half of them cannot tolerate or stick with the main treatment (CPAP or BiPAP).

Building on earlier successes, this trial tested a combo pill of atomoxetine (75 mg), an ADHD med, with aroxybutynin (2.5 mg), an antimuscarinic. Together, they stimulate the hypoglossal motor nucleus, increasing upper airway muscle tone during sleep and targeting the neuromuscular cause of obstructive sleep apnea. The combo is under development as “AD109.”

The Study

• 646 adults with mild-to-severe obstructive sleep apnea who had failed or refused PAP therapy, randomized 1:1 to AD109 or placebo across 69 U.S. and Canadian sites
• Primary endpoint: change in apnea-hypopnea index (AHI) from baseline to week 26
• Key secondary endpoints included oxygen desaturation index, hypoxic burden, and patient-reported fatigue and sleep impairment

Results

AD109 reduced apnea/hypoxia (AHI) by an estimated 44% from baseline vs 18% for placebo, a treatment difference of 4.0 events/hour. At the group level, median AHI shifted from the moderate range (19.8 events/hour) to the mild range (13.3 events/hour). About 18% of patients on AD109 achieved complete disease control (AHI below 5 events/hour) vs 9% on placebo.

Oxygenation improved significantly: the oxygen desaturation index fell by 3.7 events/hour with AD109 vs a 0.9-point increase with placebo. Hypoxic burden dropped 45% with AD109 vs 9% with placebo, though this endpoint fell outside the prespecified testing hierarchy and doesn’t reach formal statistical significance.

Fatigue did not improve more than placebo, possibly because both groups improved substantially, suggesting a strong placebo effect on subjective symptoms.

Side Effects

Dry mouth (35%), insomnia (21%), nausea (11%), and urinary hesitation (9%) were the most common adverse events. One in five patients (21%) discontinued AD109 due to side effects, vs 3% on placebo. Most discontinuations happened early. No serious adverse events.

Limitations

Industry sponsored. 34% discontinuation rate by week 26 (likely diluted the treatment effect). Dose reduction wasn’t permitted, though it might have improved tolerability. The trial didn’t screen for insomnia at baseline, which may have enriched the sample with patients prone to the drug’s most common reason for stopping.

The ADHD-Sleep Apnea Link

Around 44% of children with ADHD have obstructive sleep apnea. Sleep apnea causes most symptoms of ADHD, which improve with apnea treatment. For example, three months of CPAP treatment in adults leads to increases in gray matter volume within hippocampal and frontal structures. In children, surgery (adenotonsillectomy) is more effective than it is in adult sleep apnea.

Practice Implications

1. While most psychiatrists don’t treat sleep apnea or prescribe antimuscarinic, we do see patients who have both sleep apnea and ADHD.
2. In those cases, treat the underlying disorder, and consider atomoxetine. In an earlier trial, it improved apnea-hypoxia significantly on its own (though the antimuscarinic added to the benefit).
3. Learn more in our Carlat article on new combination therapies.