GABA is known to promote sleep and decreased consciousness, and many patients with CNS hypersomnia have been found to have endogenous GABA-A receptor hyper-reactivity. Flumazenil, a known GABA-A antagonist, has been shown to reduce symptoms in these patients, but its use may be impractical; therefore, other therapeutic options are sought. Clarithromycin, an antibiotic, is known to have neurological side effects and has recently been shown in vitro to be a GABA antagonist. The purpose of this retrospective review is to determine if clarithromycin can decrease the symptoms of GABA-A related hypersomnias, which are often refractory to currently available treatments.
The authors selected all the patients from their tertiary referral clinic who met DSM-IV criteria for narcolepsy or primary hypersomnia (excluding those with definite cataplexy and/or hypocretin deficiency), who had measured CSF GABA-A hyper-reactivity, and who had tried clarithromycin for their treatment-refractory hypersomnia. They then reviewed the electronic medical record for patients’ subjective clinical improvement and psychomotor vigilance task (PVT) improvement while on clarithromycin.
Fifty-three patients met criteria for inclusion in this study: 72% female; mean age 35; 41 with primary hypersomnia (2 of these with KLS); and 12 with narcolepsy without cataplexy. These patients had all undergone a 2-week trial period of clarithromyin 500-1000 mg with breakfast and with lunch, in which 64% had improved daytime sleepiness, 19% didn’t tolerate side effects (such as GI distress and bad taste), and 17% had no improvement. Of the patients who experienced improvement on clarithromycin, 68% chose to continue long-term treatment beyond the 2-week trial. Where PVT data was available for patients who had subjective improvement with clarithromycin, it showed a significant improvement in median reaction time while on clarithromycin.
The only significant differences between clarithromycin responders and non-responders were that responders where younger and that non-responders were on higher doses (because they didn’t respond to the starting dose). No significant differences were found between the responders and non-responders in regards to the following: gender; BMI; diagnosis; weekly sleep hours; ESS (Epworth sleepiness score); number of failed medications; history of depression; GABA-A receptor hyper-reactivity; sleep study (PSG and MSLT) results; and monotherapy vs. combination therapy.
New treatment options are needed for the large percentage of treatment-refractory patients with hypersomnia. Of the study patients, 64% showed clinical improvement with clarithromycin, and 38% chose to continue regular clarithromycin use for their disease management. Based on these results, use of clarithromycin should be considered for treatment-refractory hypersomnia associated with GABA-A receptor hyperreactivity.
The mechanism of clarithromycin’s beneficial effects in hypersomnia is not yet known. Possibilities include its GABA-A receptor antagonism, its decreased production of sleep-inducing cytokines, and changes in bacterial gut flora.
Long-term use of clarithromycin does add risks such as antibiotic resistance and superinfection, so it is important to more clearly define the benefits of its use (via a randomized controlled trial, for example) and ensure they exceed the risks. Another possible risk is cardiac; some studies have shown increased cardiac mortality with macrolide antibiotics like clarithromycin, while some have not. Drug tolerance may also develop, which may lead to decreased efficacy of the clarithromycin treatment. Finally, clarithromycin inhibits and is metabolized by the cytochrome P450 enzymes; these enzymes are necessary for metabolism and clearance of many other drugs, so changes in their function by one drug often leads to interactions with other drugs.
“Improvement in daytime sleepiness with clarithromycin in patients with GABA-related hypersomnia: Clinical experience.” by Lynn Marie Trotti, Prabhjyot Saini, Amanda A Freeman, Donald L Bliwise, Paul S García, Andrew Jenkins, and David B Rye