# Antibiotic-mediated improvements in vigilance: mechanisms of action of clarithromycin in hypersomnia syndromes

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $519,181

## Abstract

Abstract
 Excessive daytime sleepiness is a common feature of many neurologic disorders, including Parkinson’s
disease, myotonic dystrophy, and multiple sclerosis. In the neurologic disorders of hypersomnolence,
excessive daytime sleepiness occurs as the primary disease symptom, often accompanied by other sleep-
related phenomena such as long sleep durations, pronounced sleep inertia, sleep-related hallucination, and
sleep-related motor dysfunction. For two of these disorders, idiopathic hypersomnia and narcolepsy type 2,
clinical features are indistinguishable and underlying pathophysiology is unknown. However, prior work has
demonstrated that the macrolide antibiotic clarithromycin is more effective at reducing sleepiness than placebo
in these two conditions, although the mechanism or mechanisms by which clarithromycin exerts this effect are
unknown. Reduction in GABA-ergic neurotransmission, changes in resting state brain connectivity,
suppression of soporific, pro-inflammatory cytokines, and alterations in gastrointestinal microbiome
composition are all biologically plausible mechanisms for this effect, but have not been directly tested. In this
work, a randomized, placebo-controlled trial of clarithromycin will be performed in patients with idiopathic
hypersomnia and narcolepsy type 2 to evaluate for mediators of the beneficial effects of clarithromycin on
pathologic sleepiness. The first aim is to identify central nervous system mediators of reduction in sleepiness
by clarithromycin, including modulation of GABA-A receptor activity by cerebrospinal fluid in vitro and changes
in default mode network connectivity via resting state fMRI. The second aim is to probe extra-neuronal
mechanisms by which clarithromycin may reduce sleepiness, including changes in systemic inflammation and
changes in gastrointestinal microbiota composition. For all aims, sleepiness will be characterized in a multi-
modal fashion, with both self-reported measures of sleepiness, primarily the Epworth Sleepiness Scale, and
objective measures of sleepiness, primarily the mean sleep latency measured on the Maintenance of
Wakefulness Test. Each of the proposed mechanisms will be evaluated in relation to change in measures of
sleepiness via mediation analysis to determine which mechanisms mediate clarithromycin’s reduction in
sleepiness. This work leverages the PI and co-investigators’ clinical research expertise in the
hypersomnolence disorders, the unique and highly motivated patient population at the Emory Sleep Center,
and the complimentary expertise of a team of experienced collaborators. This work will impact the
understanding of the central disorders of hypersomnolence and provide a foundation for future drug
development for these and other neurologic disorders manifesting with pathologic daytime sleepiness.

## Key facts

- **NIH application ID:** 10685574
- **Project number:** 5R01NS111280-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Lynn Marie Trotti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $519,181
- **Award type:** 5
- **Project period:** 2019-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10685574

## Citation

> US National Institutes of Health, RePORTER application 10685574, Antibiotic-mediated improvements in vigilance: mechanisms of action of clarithromycin in hypersomnia syndromes (5R01NS111280-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10685574. Licensed CC0.

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