Clarithromycin for the Treatment of Hypersomnia
| Status: | Completed |
|---|---|
| Conditions: | Insomnia Sleep Studies, Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 11/8/2017 |
| Start Date: | July 2010 |
| End Date: | September 2012 |
The term 'hypersomnia' describes a group of symptoms that includes severe daytime sleepiness
and sleeping long periods of time (more than 10 hours per night). Sometimes, hypersomnia is
caused by a problem with the quality of sleep occurring at night, for instance when nighttime
sleep is disrupted by frequent breathing pauses. In other cases, however, hypersomnia occurs
even when nighttime sleep is of good quality. These cases of hypersomnia are presumed to be a
symptom of brain dysfunction, and so are referred to as hypersomnias of central (i.e., brain)
origin.
The causes of most of these central hypersomnias are not known. However, our group has
recently identified a problem with the major brain chemical responsible for sedation, known
as GABA. In a subset of our hypersomnia patients, there is a naturally-occurring substance
that causes the GABA receptor to be hyperactive. In essence, it is as though these patients
are chronically medicated with Valium (or Xanax or alcohol, all substances that act through
the GABA system), even though they do not take these medications.
Current treatment of central hypersomnias is limited. For the fraction of cases with
narcolepsy, there are FDA-approved, available treatments. However, for the remainder of
patients, there are no treatments approved by the FDA. They are usually treated with
medications approved for narcolepsy, but sleep experts agree that these medications are often
not effective for this group of patients.
Based on our understanding of the GABA abnormality in these patients, we evaluated whether
clarithromycin (an antibiotic approved by the FDA for the treatment of infections) would
reverse the GABA abnormality. In a test tube model of this disease, clarithromycin does in
fact return the function of the GABA system to normal. The investigators have treated a few
patients with clarithromycin and most have felt that their hypersomnia symptoms improved with
this treatment.
To determine whether clarithromycin is truly beneficial for central hypersomnia, this study
will compare clarithromycin to an inactive pill (the placebo). All subjects will receive both
clarithromycin and the placebo at different times, and their reaction times and symptoms will
be compared on these two treatments to determine if one is superior. If this study shows that
clarithromycin is more effective than placebo in the treatment of hypersomnia, it will
identify a potential new therapy for this difficult-to-treat disorder.
and sleeping long periods of time (more than 10 hours per night). Sometimes, hypersomnia is
caused by a problem with the quality of sleep occurring at night, for instance when nighttime
sleep is disrupted by frequent breathing pauses. In other cases, however, hypersomnia occurs
even when nighttime sleep is of good quality. These cases of hypersomnia are presumed to be a
symptom of brain dysfunction, and so are referred to as hypersomnias of central (i.e., brain)
origin.
The causes of most of these central hypersomnias are not known. However, our group has
recently identified a problem with the major brain chemical responsible for sedation, known
as GABA. In a subset of our hypersomnia patients, there is a naturally-occurring substance
that causes the GABA receptor to be hyperactive. In essence, it is as though these patients
are chronically medicated with Valium (or Xanax or alcohol, all substances that act through
the GABA system), even though they do not take these medications.
Current treatment of central hypersomnias is limited. For the fraction of cases with
narcolepsy, there are FDA-approved, available treatments. However, for the remainder of
patients, there are no treatments approved by the FDA. They are usually treated with
medications approved for narcolepsy, but sleep experts agree that these medications are often
not effective for this group of patients.
Based on our understanding of the GABA abnormality in these patients, we evaluated whether
clarithromycin (an antibiotic approved by the FDA for the treatment of infections) would
reverse the GABA abnormality. In a test tube model of this disease, clarithromycin does in
fact return the function of the GABA system to normal. The investigators have treated a few
patients with clarithromycin and most have felt that their hypersomnia symptoms improved with
this treatment.
To determine whether clarithromycin is truly beneficial for central hypersomnia, this study
will compare clarithromycin to an inactive pill (the placebo). All subjects will receive both
clarithromycin and the placebo at different times, and their reaction times and symptoms will
be compared on these two treatments to determine if one is superior. If this study shows that
clarithromycin is more effective than placebo in the treatment of hypersomnia, it will
identify a potential new therapy for this difficult-to-treat disorder.
Central hypersomnias are characterized by severe excessive daytime sleepiness despite long
sleep periods (>10 hours/night) and the absence of nocturnal sleep pathology. They
preferentially affect young adults, may result in loss of employment, and can lead to motor
vehicle accidents (1). Despite these health, safety, and quality of life consequences, there
are no FDA-approved therapies for several forms of central hypersomnia, including idiopathic
hypersomnia (IH). Currently, IH is treated using therapies approved for narcolepsy, despite a
lack of clinical trial data and a consensus that treatment response is poor (2). Treatments
include traditional psychostimulants (e.g., amphetamine derivatives) as well as
wake-promoting agents with unknown mechanisms of action such as modafinil and sodium oxybate.
In addition to side effects including high abuse potential, tachycardia, and altered mental
status, treatments are often ineffective and substantial residual sleepiness frequently
persists despite poly-therapy.
The investigators hypothesize that pathology in the GABA neurotransmitter system, the brain's
major inhibitory system, underlies these central hypersomnias. Currently, there are no
hypersomnia therapies that are GABA-antagonists. However, the macrolide antibiotic
clarithromycin has been shown to have GABA-modulating properties, resulting in the
development of insomnia or mania in a subset of patients. Clarithromycin is therefore a
potentially viable, promising therapeutic agent for hypersomnia related to positive
modulation of the GABAA receptor. Open-label use of clarithromycin in six hypersomnia
patients with known (n = 4) or suspected (n = 2) excess GABAA potentiation resulted in marked
improvements in vigilance, as measured on the psychomotor vigilance task (PVT) (unpublished
data). The investigators therefore propose a pilot, crossover trial comparing clarithromycin
to placebo for the treatment of hypersomnia in patients with excess GABAA potentiation. The
primary endpoint will be a decrease in PVT reaction time. Secondary endpoints will include a
decrease in PVT lapses and changes in Epworth, Stanford, and FOSQ sleep scales. Successful
results from this trial would provide early evidence for a more rational and efficacious
treatment for hypersomnia that could avoid the potential abuse, toxicities, and treatment
failures associated with traditional treatments.
This will be a pilot crossover trial of clarithromycin and placebo to treat central
hypersomnia. Subjects who are untreated for hypersomnia or who experience persistent symptoms
despite traditional therapies will be eligible. Subjects who are on medication for
hypersomnia at the beginning of the study will be asked to maintain stable doses of these
medications for one month before and throughout the study period. Twenty subjects will be
assessed at baseline and one and two weeks after being on each study drug (clarithromycin 500
mg bid and matched placebo bid). After two weeks on study drug, they will undergo a one week
washout period, then change to the other study drug for an additional two weeks. Patients
will be randomized to order of presentation of study drugs such that ten subjects will be
randomized to each group. Random sequence generation will be performed our pharmacy. All
study investigators and subjects will remain blinded to group assignment.
sleep periods (>10 hours/night) and the absence of nocturnal sleep pathology. They
preferentially affect young adults, may result in loss of employment, and can lead to motor
vehicle accidents (1). Despite these health, safety, and quality of life consequences, there
are no FDA-approved therapies for several forms of central hypersomnia, including idiopathic
hypersomnia (IH). Currently, IH is treated using therapies approved for narcolepsy, despite a
lack of clinical trial data and a consensus that treatment response is poor (2). Treatments
include traditional psychostimulants (e.g., amphetamine derivatives) as well as
wake-promoting agents with unknown mechanisms of action such as modafinil and sodium oxybate.
In addition to side effects including high abuse potential, tachycardia, and altered mental
status, treatments are often ineffective and substantial residual sleepiness frequently
persists despite poly-therapy.
The investigators hypothesize that pathology in the GABA neurotransmitter system, the brain's
major inhibitory system, underlies these central hypersomnias. Currently, there are no
hypersomnia therapies that are GABA-antagonists. However, the macrolide antibiotic
clarithromycin has been shown to have GABA-modulating properties, resulting in the
development of insomnia or mania in a subset of patients. Clarithromycin is therefore a
potentially viable, promising therapeutic agent for hypersomnia related to positive
modulation of the GABAA receptor. Open-label use of clarithromycin in six hypersomnia
patients with known (n = 4) or suspected (n = 2) excess GABAA potentiation resulted in marked
improvements in vigilance, as measured on the psychomotor vigilance task (PVT) (unpublished
data). The investigators therefore propose a pilot, crossover trial comparing clarithromycin
to placebo for the treatment of hypersomnia in patients with excess GABAA potentiation. The
primary endpoint will be a decrease in PVT reaction time. Secondary endpoints will include a
decrease in PVT lapses and changes in Epworth, Stanford, and FOSQ sleep scales. Successful
results from this trial would provide early evidence for a more rational and efficacious
treatment for hypersomnia that could avoid the potential abuse, toxicities, and treatment
failures associated with traditional treatments.
This will be a pilot crossover trial of clarithromycin and placebo to treat central
hypersomnia. Subjects who are untreated for hypersomnia or who experience persistent symptoms
despite traditional therapies will be eligible. Subjects who are on medication for
hypersomnia at the beginning of the study will be asked to maintain stable doses of these
medications for one month before and throughout the study period. Twenty subjects will be
assessed at baseline and one and two weeks after being on each study drug (clarithromycin 500
mg bid and matched placebo bid). After two weeks on study drug, they will undergo a one week
washout period, then change to the other study drug for an additional two weeks. Patients
will be randomized to order of presentation of study drugs such that ten subjects will be
randomized to each group. Random sequence generation will be performed our pharmacy. All
study investigators and subjects will remain blinded to group assignment.
Inclusion Criteria:
- Hypersomnia (meeting clinical criteria for Idiopathic hypersomnia with or without long
sleep time, narcolepsy lacking cataplexy, or symptomatic hypersomnia not meeting ICSD
criteria)
- evidence for GABA-related abnormality, as demonstrated by in-house, in vitro assay
- age > 18
- high performance liquid chromatography/liquid chromatography tandem mass spectrometry
verification of the absence of exogenous benzodiazepines
Exclusion Criteria:
- Contraindications to use of clarithromycin (pregnancy, severe renal impairment,
history of QT prolongation, hypomagnesemia, hypokalemia, bradycardia, history of
myocardial infarction or cardiomyopathy, myasthenia gravis, age > 70)
- Current use of cisapride, pimozide, astemizole, terfenadine, colchicines, and
ergotamine or dihydroergotamine
- Current use of benzodiazepines or benzodiazepine-receptor agonists
- moderate or severe sleep apnea (RDI > 15/hr), severe periodic limb movement disorder
(PLMI > 30/hr)
- diagnosis of narcolepsy with cataplexy, as determined by cerebrospinal hypocretin
levels
- metabolic disorders such as anemia, severe iron deficiency, B12 deficiency, or
hypothyroidism that may explain symptoms of hypersomnia
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