Effects of lemborexant and zolpidem on sleep electroencephalography in older adults with insomnia: a randomized trial

How sleep medications affect brain physiology over time remains largely unknown. Prior pharmacodynamic work has established distinct spectral signatures of GABA-A receptor modulators vs. DORAs in younger or mixed adult samples. Here, we report how sleep EEG effects evolve from acute (days 1-2) to chronic (days 29-30) exposure in older adults with insomnia meeting DSM-5 criteria, and how within-person changes relate to Insomnia Severity Index (ISI). This analysis used data from a randomized, double-blind, placebo-controlled, active-comparator phase III trial (May 2016-January 2018). A subset of 249 participants was analyzed for EEG outcomes. Participants received 5 mg or 10 mg LEM (LEM5, LEM10), 6.25 mg extended-release zolpidem (ZOL), or placebo nightly for 30 days. Polysomnography was collected at baseline, after acute exposure, and after chronic exposure. Acute ZOL exposure produced significant increases in non-rapid eye movement (NREM) slow oscillation (SO), sigma, beta, and gamma power, with decreases in delta and theta compared to all treatment groups. These effects persisted with chronic exposure, alongside an alpha increase from acute to chronic exposure. LEM10 showed minimal acute effects but, with continued use, increased SO and decreased alpha power. The degree of SO power increase from acute to chronic exposure predicted improvements in ISI scores, driven by the LEM10 group. ZOL showed similar REM effects, whereas LEM5, but not LEM10, reduced REM sigma and beta power. These findings demonstrate that ZOL and LEM differentially modulate sleep EEG, with sustained SO enhancement under LEM10 linked to symptom improvement.