Description of the condition
Idiopathic hypersomnia is a chronic neurologic sleep disorder that manifests as excessive daytime sleepiness occurring despite normal or prolonged sleep times (i.e. exceeding 11 hours of sleep per 24-hour period), in the absence of other disorders that impair sleep quality, such as sleep apnea. Symptoms and signs of idiopathic hypersomnia also include marked sleep inertia (severe and prolonged difficulties with awakening), long and unrefreshing naps, and high measured sleep efficiency in the sleep laboratory, although some patients meeting diagnostic criteria for idiopathic hypersomnia do not endorse these classic ancillary symptoms (Bassetti 1997; Anderson 2007; ICSD-3 2014). Depressive symptoms and difficulties with concentration and attention are frequently present in patients with idiopathic hypersomnia, and quality of life is reduced (Dauvilliers 2009; Vernet 2009; Vernet 2010; Ozaki 2012).
The cause of idiopathic hypersomnia remains unknown at present, although abnormalities of sleep macro- and microstructure have been noted (Vernet 2009; Pizza 2013). Idiopathic hypersomnia, especially that without long nocturnal sleep times, shares many clinical similarities with narcolepsy without cataplexy (narcolepsy type 2) and the two disorders may be indistinguishable except for multiple sleep latency testing (MSLT) (Šonka 2015). At least two major diagnostic classification schema, the International Classification of Sleep Disorders (ICSD) and the Diagnostic and Statistical Manual of Mental Disorders (DSM), have published diagnostic guidelines for this entity, although the diagnostic criteria in the two systems are not identical. The currently preferred name in the ICSD, third edition, is "idiopathic hypersomnia" and in the DSM, fifth edition, is "hypersomnolence disorder", but other names used in the past include idiopathic central nervous system hypersomnolence, non-rapid eye movement (NREM) narcolepsy, NREM hypersomnia, primary hypersomnia, and hypersomnia with sleep drunkenness. Hypersomnia disorder (DSM, fourth edition) has a population prevalence of 0.5% in the United States (Ohayon 2013).
Description of the intervention
Multiple medications have been used in clinical practice for the treatment of idiopathic hypersomnia. Many of these medications are known or are suspected to be effective in treating excessive daytime sleepiness in other disorders, such as narcolepsy or obstructive sleep apnea, and then are extended for use in idiopathic hypersomnia with or without specific testing in patients with that disorder. Clinical series suggest that this strategy results in satisfactory symptom control in the majority of patients, with a poorer response to treatment in up to one third (Bassetti 1997; Anderson 2007; Ali 2009). Medication classes that have been used in the treatment of idiopathic hypersomnia include amphetamines, non-amphetamine wake-promoting agents (e.g., modafinil, mazindol), histamine H3 antagonists/inverse agonists, GABA-B/gamma hydroxybutyrate agonists, levothyroxine, alerting antidepressants such as bupropion, melatonin (for sleep inertia) and GABA-A antagonists (Montplaisir 2001; Morgenthaler 2007; Shinno 2011; Rye 2012; Nittur 2013; Leu-Semenescu 2014; Trotti 2015; Trotti 2016; Leu-Semenescu 2016).
How the intervention might work
Amphetamines increase the release and block the reuptake of monoaminergic neurotransmitters (i.e. dopamine, norepinephrine, and serotonin) and their effects on dopaminergic neurotransmission are particularly important for their effects at promoting wakefulness (Banerjee 2004; Gowda 2014). Multiple potential mechanisms of action have been proposed for modafinil, including effects on dopaminergic neurotransmission (Banerjee 2004; Gowda 2014). The alerting potential of mazindol and bupropion may also be related to their actions as dopamine reuptake inhibitors (Heal 2014). Histamine H3 antagonists/inverse agonists promote wakefulness by increasing central nervous system histamine levels (Leu-Semenescu 2014). The mechanism by which agonists of GABA-B/gamma hydroxybutyrate reduce sleepiness is not known, although deep sleep is increased (Gowda 2014). Levothyroxine might improve alertness via hormonal effects or by increasing central nervous system histamine levels (Shinno 2011). Because patients with idiopathic hypersomnia tend to have a circadian phase delay, evening use of melatonin has been proposed as a method of advancing the circadian rhythm and improving sleep inertia (Vernet 2009). GABA-A antagonists have been used in patients with idiopathic hypersomnia based on the finding of a positive allosteric modulator of GABA-A receptors within the cerebrospinal fluid of hypersomnolent patients (Rye 2012) and the known sleep-promoting effects of the GABA-A system (Lu 2006).
Why it is important to do this review
There are currently no medications approved for the treatment of idiopathic hypersomnia by the United States Food and Drug Administration, thus all pharmacologic treatment of patients with idiopathic hypersomnia in the United States is 'off-label'. The European Medicines Agency has explicitly stated that modafinil should only be used in patients with narcolepsy, not in patients with idiopathic hypersomnia (EMA Modafinil 2010), although modafinil is one of the medications recommended for treatment of idiopathic hypersomnia in expert consensus guidelines (Morgenthaler 2007). As a result of this disagreement and lack of regulatory approval, clinical decision-making regarding treatment of idiopathic hypersomnia can be challenging. Furthermore, the medications used for the treatment of idiopathic hypersomnia carry risk for serious side effects or medication interactions, including but not limited to addiction (amphetamines), respiratory depression or coma (sodium oxybate), superinfection and antibiotic resistance (the GABA-A receptor antagonist clarithromycin), and reduced efficacy of hormonal birth control (modafinil, armodafinil) (Trotti 2013; Krahn 2015). Patients and prescribers must carefully weigh the trade-offs of risk and benefit when choosing a treatment option.