Antibiotic May Decrease EDS in GABA-related Hypersomnia

clariA study of clarithromycin in the treatment of GABA-related hypersomnia indicates that this drug may be effective in some patients with idiopathic hypersomnia (IH), narcolepsy without cataplexy, and subjective hypersomnia.BackgroundThe US Food and Drug Administration (FDA) has not approved any drugs for the treatment of IH. Therefore, current treatments are all prescribed off label, meaning that the FDA has approved the drug for some other purpose but not for IH.

As reported in 2012, researchers at Emory University discovered that the cerebrospinal fluid of many of their patients with central disorders of hypersomnolence contained an unknown substance that, when tested in the laboratory, enhances the action of GABA (gamma-aminobutyric acid, the main inhibitory neurotransmitter) in a way similar to that of benzodiazepines or sleeping pills, such as Valium or Ambien. The researchers termed this a “somnogen” and the resulting disorder, “GABA-related hypersomnia.”

The researchers then tested a treatment to counteract these sleep-enhancing effects in seven patients who had been diagnosed with GABA-related hypersomnia (two with IH, two with narcolepsy without cataplexy, and three who had “habitually long sleep”). The researchers gave all of these patients a GABAA-receptor negative allosteric modulator, flumazenil, intravenously. The patients both reported being less sleepy and improved their reaction times on the Psychomotor Vigilance Task (PVT).

In subsequent papers, the Emory researchers reported that clarithromycin, a macrolide antibiotic that is typically used to treat skin and respiratory system infections, also decreased daytime sleepiness in people with GABA-related hypersomnia.

What kind of research study was this new study?

This was a 5-week, double-blind, placebo-controlled, crossover study.

Who were the participants in this study and what did they do?

All of the participants had IH, narcolepsy without cataplexy, or habitually long sleep times. They took either clarithromycin, 500 mg, or placebo at breakfast and at lunch for two weeks. They then took no drug for one week, followed by the opposite drug that they took in the first part of the study—either clarithromycin or placebo—for another two weeks. They came to the Emory research clinic at the same time on the same day of the week for these five weeks, where they completed several questionnaires and performed two PVTs during each visit.

Who were the researchers and what did they do?

Dr. Trotti and her colleagues at Emory University in Atlanta, GA, selected the participants, reviewed the questionnaires, and analyzed the data from the PVTs.

What were the results of the study?

Fifteen women and five men took part in this study. There was no difference in mean reaction time on the PVT at week two between people’s scores when they were taking clarithromycin versus when they were taking placebo. However, significant differences were found on the results of the questionnaires. When taking clarithromycin, the participants had an average four-point lower score on the Epworth Sleepiness Scale, improved scores on the Functional Outcomes of Sleep Questionnaire, and increase in the energy subscale of the SF-36.

Those in the clarithromycin group were more likely to report an altered sense of taste or smell. Otherwise, no differences were found in side effects. These changes are similar to or better than improvements typically seen with modafinil for the treatment of excessive daytime sleepiness associated with narcolepsy or shift work disorder.

What were the authors’ conclusions?

“Clearly, the long term use of an antibiotic must be justified by clinical benefit that exceeds these potential risks, as we have elaborated elsewhere. . . This preliminary study suggests that there is a subjective treatment benefit from clarithromycin for idiopathic hypersomnia, narcolepsy without cataplexy, and subjective hypersomnia, consistent with the benefit previously reported in clinical practice. . .  “[C]larithromycin might be considered, especially in cases that are otherwise treatment-refractory.”

Trotti LM, Saini P, Bliwise DL, Freeman AA, Jenkins A, Rye DB. Clarithromycin in GABA-related hypersomnolence: a randomized, crossover trial. Ann Neurol 2015. doi: 10.1002/ana.24459. [Epub ahead of print]


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