Excessive daytime sleepiness and long sleep durations are common features of many neurologic disorders, including myotonic dystrophy, Parkinson's disease, and the central nervous system hypersomnia syndromes. These latter syndromes are a group of disorders with overlapping clinical phenotypes and, except in the case of narcolepsy due to hypocretin deficiency (narcolepsy type 1), potentially shared pathophysiology. Pathologic daytime sleepiness in these disorders impairs occupational performance, limits quality of life, and more than doubles motor vehicle and other accident risk. Because the underlying cause of the majority of these hypersomnia syndromes is not known, treatments are aimed at increasing monoaminergic signaling involved in wake promotion. Yet, at least one-fourth of patients with hypersomnia syndromes cannot achieve satisfactory control of symptoms with these treatments and disability or medical leaves of absence are often necessary. There is a clear need for novel treatments for excessive daytime sleepiness to resolve this failure of the current standard of care. In prior studies, clarithromycin resulted in significant, clinically meaningful improvements in sleepiness severity, sleepiness-related limitations in extended activities of daily living, and sleepiness-related quality of life. Long sleep durations and sleep inertia, both ancillary symptoms of hypersomnia disorders that contribute to functional impairments, were also improved with clarithromycin. Hypothesis: Clarithromycin will reduce excessive sleepiness and other symptoms of hypersomnia disorders, as measured by self-report and objective testing. Aim 1: To identify central nervous system mediators of clarithromycin's ability to promote wakefulness and reduce sleepiness, among patients with central hypersomnia syndromes. Hypothesis 1a: Changes in cerebrospinal fluid (CSF) enhancement of gamma-aminobutyric acid-A (GABA-A) receptor function in vitro will be associated with improvements in self-reported and objectively measured sleepiness. Hypothesis 1b: Changes in functional connectivity will be associated with improvements in self-reported and objectively measured sleepiness. Aim 2: To probe extra-neuronal mechanisms by which clarithromycin may reduce sleepiness, including changes in systemic inflammation and changes in gastrointestinal microbiota composition, in patients with central hypersomnia syndromes. Hypothesis 2a: Improvement in sleepiness with clarithromycin use will be positively associated with reductions in systemic inflammation, especially reductions in levels of tumor necrosis factor-alpha (TNFα). Hypothesis 2b: Improvement in sleepiness with clarithromycin use will be positively correlated with modulation of gastrointestinal dysbiosis.
Inclusion Criteria: - diagnosis of idiopathic hypersomnia or narcolepsy type 2 - age 18-45 (with the upper limit established because of age-dependent changes in DMN resting state functional magnetic resonance imaging connectivity (rs-fMRI) connectivity and to minimize risk of side effects) - free of wake-promoting medication or willing to discontinue current wake-promoting medication for at least 5 half-lives prior to baseline measures - free of pre- or probiotic supplements for at least six months prior to baseline measures Exclusion Criteria: - other potential causes of hypersomnolence, including moderate or severe sleep apnea, severe periodic limb movement disorder with arousals, uncontrolled metabolic disorders, hypocretin deficiency, or cataplexy - contraindication to clarithromycin - contraindication to any of the study procedures