Clarithromycin in γ-aminobutyric acid-Related hypersomnolence: A randomized, crossover trial

Abstract

Objective: Some central hypersomnolence syndromes are associated with a positive allosteric modulator of γ-aminobutyric acid (GABA)-A receptors in cerebrospinal fluid. Negative allosteric modulators of GABA-A receptors, including clarithromycin, have been reported to reduce sleepiness in these patients. We sought to systematically assess the effects of clarithromycin on objective vigilance and subjective sleepiness.

Methods: This was a 5-week, randomized, placebo-controlled, double-blind, crossover trial of clarithromycin 500mg with breakfast and lunch, in patients with hypersomnolence syndromes (excluding narcolepsy with cataplexy) and evidence for abnormal cerebrospinal fluid potentiation of GABA-A receptors. The study occurred at a university-affiliated medical center. The primary outcome measure was median reaction time on the psychomotor vigilance task (PVT) at week 2 in each condition. Secondary outcomes included the Epworth Sleepiness Scale, Stanford Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, Pittsburgh Sleep Quality Index, SF-36, and additional PVT measures.

Results: Twenty-three patients began treatment. Three patients dropped out, and final analyses were performed on 20 complete cases. Median reaction time was not significantly different between clarithromycin and placebo. Subjective measures of sleepiness were significantly improved on clarithromycin versus placebo. Altered taste perception occurred, but was the only side effect more common on clarithromycin than placebo. No serious adverse events occurred.

Interpretation: Subjective sleepiness, but not psychomotor vigilance, improved during a 2-week course of clarithromycin. Although additional studies are needed, this suggests that clarithromycin may be a reasonable treatment option in patients with treatment-refractory hypersomnolence. This trial was registered at ClinicalTrials.gov (NCT01146600) and supported by the American Sleep Medicine Foundation.

Conflict of interest statement

Potential Conflicts of Interest

Dr. Trotti, Mr. Saini, and Dr. Freeman have no potential conflicts to report. Dr. Jenkins and Dr. Rye have a U.S. patent application (U.S. 20110028418A1) pending for the use of GABA-A receptor antagonists for the treatment of hypersomnia and other disorders of excessive sleepiness. Dr. Bliwise reports personal fees from New England Research Institute, Ferring Pharmaceuticals, Morehouse School of Medicine, Vantia Therapeutics, Merck, and Georgia Institute of Technology, outside the submitted work. Dr. Rye reports personal fees from Jazz Pharmaceuticals, UCB Pharma, and Xenoport Inc., outside the submitted work.

© 2015 American Neurological Association.

Figures

Figure 1. Study protocol

Subjects were randomized to order of presentation of clarithromycin (vertical lines) and placebo (checkerboard).

Figure 2

Flow diagram of study participants

Figure 3. Clarithromycin versus placebo

All panels are boxplots demonstrating individual subject values while taking clarithromycin or placebo. Subjects randomized to clarithromycin first are indicated by pluses and those randomized to placebo first are indicated by open circles. Mean values are indicated by filled triangle and baseline values are indicated by the horizontal dashed line. Median values are indicated by the solid horizontal line inside the box, and the 25th and 75th percentiles are indicated by the upper and lower edges of the box. For median reaction time (A) and Epworth sleepiness scale (B), lower values indicate less impairment of vigilance/less sleepiness. For Functional Outcomes of Sleep (C) and SF-36 Energy (D), higher values indicate less severe impact of symptoms.