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 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 five-week, randomized, placebo-controlled, double-blind, crossover trial of clarithromycin 500 mg 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, Pittsburgh Sleep Quality Index, the SF-36, and additional PVT measures. Results Twenty-three patients began treatment. Three patients dropped out, and final analyses were performed on twenty 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 two-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.

New developments in the management of narcolepsy

“…Clarithromycin 500 mg twice a day for 5 weeks significantly reduced daytime sleepiness with a four-point reduction in ESS, significantly improved Functional Outcomes of Sleep Questionnaire scores, and significantly improved SF-36 energy section scores in 20 hypersomnolent nonnarcoleptic–cataplectic patients, 4 of whom had Type 2 narcolepsy, when compared to the placebo group. There was no difference in median reaction time on the psychomotor vigilance task between the two groups 54. The improvements seen with clarithromycin therapy appear modest, and chronic use of an antibiotic with possible emergence of drug-resistant bacteria does not appear warranted.…”

Idiopathic Hypersomnia

“…A number of different classes of medications have been proposed for the treatment of IH, including: GABA-A receptor antagonists/negative modulators (clarithromycin and flumazenil), GABA-B/gamma hydroxybutyrate receptor agonists, histamine H3 inverse agonists, levothyroxine, non-amphetamine stimulants, and transcranial direct stimulation (see Table 5 for details). Of these interventions, only clarithromycin has been evaluated in an RCT including patients with IH (13). In this study, clarithromycin 500 mg taken with breakfast and lunch resulted in a significant improvement in Epworth Sleepiness Scale scores and other subjective measures of IH symptoms, but did not improve psychomotor vigilance (13).…”

“…Although this enhancement of GABAergic transmission has not been shown to be causal to sleepiness or long sleep durations in patients with IH, biological plausibility is demonstrated by the known GABAergic mechanisms of sleep onset and maintenance, as well as the prominent role of GABA-A receptor agonists/modulators in the production of pharmacologic sleep and anesthesia (9–12). Further, symptoms of IH are reversible in some patients with use of GABA-receptor antagonists or negative allosteric modulators (see Treatment Resistance , below) (8, 13, 14). …”

Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [11C]Flumazenil PET

“…Therefore, orally administered negative allosteric moderators/antagonists of GABA A receptors have been explored as alternative treatments. 5,6 Clarithromycin ( Figure 2), a macrolide antibiotic approved in both oral and intravenous forms, has a range of neurotoxic side effects, including excitation, mania, psychosis, insomnia, and nonconvulsive status epilepticus. 7−10 Although the mechanism of action underlying these CNS side effects is unknown, 7 clarithromycin is purported to be a negative allosteric modulator of GABA A receptors from in vitro wholecell patch clamp experiments, albeit with low affinity (18% and 45% inhibition at 3 and ∼300 μM, respectively).…”