Psychiatric Annals

CME 

Hypersomnolence Disorders in DSM-5: A Review for Clinicians

Elliott Kyung Lee, MD, FRCPC; Louis Kazaglis, MD

Abstract

Hypersomnolence disorders, encompassing both hypersomnolence and narcolepsy with or without hypocretin deficiency, have undergone a major update in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). This update captures the paradigm shift that has advanced the understanding of these sleep disorders and their biological underpinnings. This article reviews the updated classification of hypersomnolence disorders in DSM-5. The prevalence, neuroanatomical basis, and clinical symptoms of these disorders are also explored. Hypersomnolence disorders can now be diagnosed comorbidly with other mental health disorders. This article explores this overlap and bidirectional relationship, along with the relationship between hypocretin deficiency and other mental health disorders. Finally, treatment strategies for hypersomnolence disorders and cataplexy are covered, including both behavioral and pharmacologic therapies. Traditional therapies and their proposed mechanisms of action are discussed, followed by a brief review of novel therapeutic agents undergoing clinical evaluation. Finally, recommendations for further exploration are reviewed. [Psychiatr Ann. 2015;45(1):25–29.]

Abstract

Hypersomnolence disorders, encompassing both hypersomnolence and narcolepsy with or without hypocretin deficiency, have undergone a major update in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). This update captures the paradigm shift that has advanced the understanding of these sleep disorders and their biological underpinnings. This article reviews the updated classification of hypersomnolence disorders in DSM-5. The prevalence, neuroanatomical basis, and clinical symptoms of these disorders are also explored. Hypersomnolence disorders can now be diagnosed comorbidly with other mental health disorders. This article explores this overlap and bidirectional relationship, along with the relationship between hypocretin deficiency and other mental health disorders. Finally, treatment strategies for hypersomnolence disorders and cataplexy are covered, including both behavioral and pharmacologic therapies. Traditional therapies and their proposed mechanisms of action are discussed, followed by a brief review of novel therapeutic agents undergoing clinical evaluation. Finally, recommendations for further exploration are reviewed. [Psychiatr Ann. 2015;45(1):25–29.]

The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) classification of hypersomnolence disorders is a paradigm shift from the DSM, fourth edition, text revision (DSM-IV-TR). DSM-5 was designed for use by mental health professionals who, in the majority of cases, would not have a sleep medicine background and thus would need a simplified view of these disorders. Compared with DSM-IV-TR, the hypersomnolence diagnoses of DSM-5 are significantly more driven by empirical data and represent an attempt to use more biological markers for psychiatric illness, as is evident in the criteria for narcolepsy.

Most epidemiologic studies assessing hypersomnolence have only been done in this century. A large epidemiologic study using a validated telephone survey of 15,929 individuals suggested that hypersomnia disorder is present in 1.5% of the population, whereas excessive sleepiness is reported by 27.8% of the population.1 It is from these data that thresholds were determined for clinically significant hypersomnia, as evidenced by the DSM-5 criteria: “three times per week for at least 3 months,” “significant distress,” and “not attributable to the physiologic effects of substance or [other] disorder.”2 Together these criteria brought the prevalence down to 1.5%.

A fundamental shift in DSM-5 is that psychiatrists can now diagnose a hypersomnolence disorder in addition to another psychiatric disorder. This can frequently be seen in clinical practice, where a patient may present with a major depressive disorder (MDD) for instance, and sleepiness. The patient could be treated for the underlying depressive disorder, but hypersomnolence may persist. In DSM-IV-TR, this patient would be diagnosed with “sleep disorder related to another mental disorder” whereas in DSM-5, they could be diagnosed with both a depressive and comorbid hypersomnolence disorder, and treated accordingly.3 This paradigm shift in DSM-5 was done in recognition of the concept that sleep, psychiatric, and medical disorders frequently can have a bidirectional relationship.

In DSM-5, hypersomnolence disorders are divided into two main groups: 1) hypersomnolence without evidence of hypocretin abnormalities; and 2) narcolepsy, with or without hypocretin deficiency and/or cataplexy and/or associated with other medical condition.4 The first group is the most frequent and most challenging for treatment. A splitting approach was used for hypersomnolence disorders based on empirical data.3 This is particularly evident in the specifiers for narcolepsy, where five subtypes are delineated. These subtypes are identified by empirical data but represent a very small subset of patients with narcolepsy. The vast majority of narcolepsy patients will meet only the primary criteria identified in DSM-5 and will be the focus of the remainder of this discussion.

Hypersomnia Case

A 28-year-old female with a history of obesity and MDD that is well controlled on sertraline 100 mg daily presents with concerns of ongoing tiredness despite resolution of depressive symptoms. On further history, she clarifies tiredness as a profound daytime sleepiness even with adequate sleep of 8 hours per night. This problem preceded her diagnosis of MDD by several years. She reports that 6 months ago she almost had a car accident when she drove through a stop sign due to drowsiness. The sleepiness is accompanied by occasional episodes in which the patient hears someone calling her name upon waking, even though she lives alone. She denies any other hallucinations. She denies a history of seizures or head trauma, but reports she gets embarrassed by occasional episodes of bilateral hand weakness upon hearing a particularly entertaining joke. There is no reported snoring from family members, and the patient denies any nocturnal leg discomfort.

Narcolepsy: Clinical Symptoms

The prevalence of narcolepsy (with or without cataplexy) is approximately 0.04%.5 The “pentad” of symptoms associated with narcolepsy includes excessive daytime sleepiness, disturbed nighttime sleep, sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy. Beyond this pentad, several other conditions are associated with narcolepsy, including rapid eye movement (REM) sleep behavior disorder, periodic limb movements, and sleep-disordered breathing.6–8 Age of symptom onset can occur from early childhood to the fifth decade, with a bimodal distribution peaking at 15 and 35 years.6

The primary clinical symptom of narcolepsy is excessive daytime sleepiness, which frequently manifests as inadvertent sleep attacks lasting seconds to minutes in problematic situations. This symptom is associated, somewhat counterintuitively, with frequent arousals during night sleep. This sleep fragmentation is thought to occur due to wakefulness intruding upon sleep. In half of patients with narcolepsy, this sleep fragmentation is accompanied by automatic behaviors during which patients initiate purposeful behavior (eg, walking, yelling, eating) with no recollection of this upon awakening.6 Furthermore, REM intrusion phenomena such as sleep paralysis or hypnagogic/hypnopompic hallucinations may be seen. Sleep paralysis is characterized by an inability to move despite being consciously aware of one’s surroundings, usually upon awakening although it can occur at sleep onset. This occurs due to the normal paralysis of REM sleep intruding upon wakefulness. Hallucinations can occur either upon sleep onset (hypnagogic) or offset (hypnopompic) and are often multimodal in nature. These are thought to occur due to the dream phenomena of REM sleep intruding upon wakeful-ness. Both sleep paralysis and hypnagogic/hypnapompic hallucinations occur in up to two-thirds of patients with narcolepsy, but are not specific,6 as they can also be seen in the general population: 6.1% for sleep paralysis and 24.1% for hypnagogic/hypnapompic hallucinations.5

Cataplexy, however, is virtually pathognomonic for narcolepsy. It is an episode of bilateral muscle atonia lasting seconds to minutes, usually triggered by a strong emotion. Common triggers include laughter, joy, anger, or surprise. In some cases, there is profound loss of muscle tone leading to collapse to the ground, whereas in others the paralysis is subtle and can include slurring of speech, head-nodding, or knees buckling. Patients are fully conscious in these episodes (unlike sleep attacks). This symptom can be debilitating, affecting activities of daily living such as driving, or recreational activities such as swimming.9,10 In half of patients with narcolepsy, cataplexy will be present at the time of diagnosis, whereas of the remaining half, 40% will go on to develop cataplexy within 5–10 years.6,9 Overall, this implies a cataplexy prevalence of 70% among patients with narcolepsy. Despite the impact of narcolepsy on quality of life, both physician and public awareness of the illness is low.9,10

Neuroanatomical Considerations: Hypersomnolence

The sleep-promoting system of the brain includes neurons from the ventrolateral preoptic nucleus, mediated primarily by gamma-amino butyric acid (GABA) and galanin. These peptides are inhibitory to the arousal system. The arousal system consists primarily of noradrenergic neurons in the locus coeruleus, serotonergic dorsal raphe, dopaminergic ventral periaqueductal gray matter, and histaminergic tuberomamillary nucleus. Both the sleep-promoting and arousal systems are innervated by orexinergic neurons arising from the posterolateral hypothalamus, which act as mediators of this “flip-flop” switch from sleep to wakefulness, and from non-REM sleep to REM sleep.11 With these systems intact, the transition from sleep to wakefulness takes only seconds to minutes, with less than 2% of a day spent in a transition state.11 The wiring of these neurons makes a transition from wakefulness directly to REM sleep almost impossible because of the excitatory activity of orexin to REM sleep-off systems, including the monoaminergic arousal systems.12

Narcolepsy with Cataplexy: Etiologic Considerations

Recent research has demonstrated compelling evidence that narcolepsy with cataplexy is strongly associated with a deficiency of orexin/hypocretin neurons.13,14 The names “hypocretin” and “orexin” are used interchangeably, reflecting the nearly simultaneous discovery of this neuropeptide by two independent laboratories using two different approaches.15 The hypocretinergic neurons produce two peptides with a high degree of homology: hypocretin-1 and hypocretin-2, sometimes also called orexin-A and orexin-B.16 More than 90% of patients suffering from narcolepsy with cataplexy have low or undetectable levels of cerebrospinal fluid (CSF) hypocretin,9 and this is associated with a positive test for several human leukocyte antigens (HLA), including HLA-DQB1*0602.6 In patients suffering from narcolepsy with cataplexy, 90% are positive for this antigen, in contrast to only 12%–34% of the normal population.6 In patients suffering from narcolepsy without cataplexy, only 40% are positive for this antigen, making the association less certain. DNA testing for HLA-DQB1*0602 can be useful to evaluate patients suspected of having narcolepsy with cataplexy. If a negative result is obtained, it is unlikely the patient has narcolepsy with cataplexy. A positive result, however, is less useful, because of the high prevalence of the antigen in a normal population.

These characteristics have made narcolepsy the first DSM diagnosis for which diagnostic criteria now include a laboratory (CSF hypocretin) test value,2 although this test is not routinely available in most hospitals. The selective loss of hypocretin neurons is strongly suspected to be autoimmune in origin.17 Vulnerability has been associated with several upper respiratory tract infections including Streptococcus pyogenes and the influenza A virus. A recent spike of newly reported cases of narcolepsy was seen with the 2009 H1N1 pandemic in China.18 Subsequent investigations also suggested that new-onset cases of narcolepsy in Europe were associated with the Pandemrix flu vaccine (GSK, London, UK) developed in response to the 2009 H1N1 pandemic.17 In contrast, flu vaccines in the United States did not demonstrate a comparable relationship to the onset of narcolepsy. Several investigators have hypothesized that some T cells can be activated by certain H1N1 epitopes, leading to the selective destruction of hypocretin cells, providing further evidence for an autoimmune etiology for narcolepsy.16

Hypocretin and Psychiatric Disorders

Hypocretin has been implicated in several psychiatric disorders, including mood, anxiety, substance use, and psychotic disorders. Patients with narcolepsy have a higher frequency of MDD and social anxiety disorder,7 as well as panic attacks.19 Some data suggest binge eating behaviors occur more frequently in patients with narcolepsy.20 The majority of narcolepsy patients are overweight and at risk for associated conditions such as cardiovascular disease, hypercholesterolemia, hypertension, and obstructive sleep apnea.7 Some investigators have suggested a link between narcolepsy and psychotic disorders.21 This relationship is complicated because hypnagogic/hypnapompic hallucinations can be misdiagnosed as symptoms of schizophrenia, and high doses of amphetamines used for narcolepsy treatment can induce psychosis.22 The former issue can be resolved with careful history taking; the hypnagogic/hypnopompic hallucinations of narcolepsy often involve multimodal experiences (ie, simultaneous visual, auditory, and tactile hallucinations) and typically do not have any delusional content or auditory commentary, as is often seen in schizophrenia.23 Hypocretin signaling has also been implicated in drug-seeking behavior; consequently hypocretin antagonists are being considered as novel therapies for chemical dependency treatment.24 Studies have demonstrated no association between narcolepsy and alcohol/substance use disorders.7 The aforementioned symptoms could result in narcolepsy patients initially presenting to psychiatrists, highlighting the need for awareness of this diagnosis. Several studies suggest these patients are frequently misdiagnosed with primary psychiatric disorders such as mood or personality disorders, even by psychiatrists with sleep medicine training.10

Other Hypersomnolence Disorders

Idiopathic Hypersomnia, Kleine-Levin Syndrome

These causes of hypersomnia fall under the DSM-5 diagnosis of “hypersomnolence disorders.” Little is known about these disorders. In idiopathic hypersomnia, patients will frequently present with persistent excessive daytime sleepiness and/or sleep inertia (residual grogginess/sleepiness upon awakening) despite an adequate quantity of sleep the previous night. Even prolonged daytime naps may not be restorative.6 In Kleine-Levin syndrome (KLS), patients (more frequently boys) often present in adolescence with episodic bouts of hypersomnolence, hyperphagia, and hypersexuality, with associated cognitive impairment for decades before symptoms spontaneously resolve.25

Diagnostic Strategies for Hypersomnolence Disorders

Once a history supportive of a hypersomnolence disorder has been obtained, then a diagnosis is typically established through further testing followed by integration of these results with the clinical evaluation. The diagnosis of narcolepsy can be established through the combination of a clinical evaluation and CSF hypocretin measurements, but confirmation is typically made through multiple sleep latency testing (MSLT).26 The MSLT protocol consists of modified electroencephalographic monitoring of a patient during 4 to 5 nap periods evenly spread throughout the day. The purpose of the MSLT is to assess for the propensity to fall asleep and the ability to quickly transition into REM sleep. Mean sleep latencies below 8 minutes are consistent with hypersomnolence disorders; however, patients with narcolepsy typically have latencies around 3 minutes, with values for normal controls ranging from 10 to 20 minutes. Narcolepsy is marked by early transitions into REM sleep, and among patients with narcolepsy two or more REM sleep periods are expected during the MSLT.

There are special considerations that influence the accuracy of the MSLT. Assessment of the sleep-wake schedule prior to MSLT is recommended, as both acute and chronic sleep restriction can cause false-positive test results. This can be controlled through the use of sleep journals in combination with actigraphy recording for a period of 1 to 2 weeks prior to testing. Other sleep disorders, including periodic limb movement disorder or obstructive sleep apnea, can cause objectively measureable sleepiness so a nocturnal polysomnogram (PSG) should precede the MSLT to assess for other sleep disorders. Stimulants and other wakefulness-promoting medications, including nicotine, can artificially prolong sleep latencies. Most antidepressants typically increase REM sleep latencies and decrease total REM sleep. Other medications, such as antihistamines or alpha-2 adrenergic agonists, can increase sleep propensity. Consequently, any offending agents should be stopped 2 weeks prior to the MSLT (or longer if the agent has a long half-life) to minimize medication and/or withdrawal effects. Urine drug screening is routinely used to evaluate for the presence of both prescription and illicit substances.

Treatment Options for Narcolepsy and Hypersomnolence

Treatment options for hypersomnolence and narcolepsy have usually included education and behavioral modification, as well as stimulant medications such as modafinil, armodafinil (the active Renantiomer of modafinil), and more potent stimulants such as methylphenidate and amphetamines.27 A useful behavioral modification is regularizing sleep and scheduling naps one to three times a day.4 It is also important to discuss avoiding jobs/activities where sleep and/or alertness are priorities, such as jobs where shift work or significant driving are required.4 Beyond the stimulant medications, lithium has been used for KLS with limited success, although in most cases observation is sufficient.4 Clarithromycin has been used infrequently for treatment of some hypersomnolence disorders, with benefits being attributed to the benzodiazepine antagonist-like properties of this drug.4

The aforementioned stimulant medications primarily act by increasing dopamine availability at the synaptic level to promote wakefulness. Modafinil and armodafinil also may increase availability of other monoamines and histamine, which may contribute further to wakefulness-promoting properties.28 For cataplexy and other REM intrusion phenomena, treatments usually involve REM-suppressing medications that block the reuptake of serotonin and norepinephrine preferentially, such as the serotonin-norepinephrine reuptake inhibitors or other tricyclic antidepressants with comparable activity,26 although selective serotonin reuptake inhibitors (SSRIs) with adrenergic activity such as fluoxetine are also effective. In educational lectures, we have referred to SSRIs as “super selective REM inhibitors” to help reinforce that these medications suppress REM sleep. Atomoxetine, a selective noradrenergic inhibitor, has also been used with some success for cataplexy.26 The most powerful anticataplectic agent currently is sodium oxybate (also known as gamma hydroxybutyrate or GHB), which is a GABA-B agonist,but likely also affects dopamine, serotonin, and endogenous opioids. This agent is effective for daytime sleepiness and cataplexy. It may work by consolidating night sleep, resulting in fewer daytime sleep (especially REM sleep) intrusions, but the method of action is not entirely clear.3 With the aforementioned treatment measures, up to 80% of patients with narcolepsy can return to near normal functioning.4

Novel Agents

Newer therapeutic agents being evaluated for narcolepsy with cataplexy include intranasal hypocretin.9 R-baclofen also shows promise for cataplexy in a murine model, but one study on humans did not show any efficacy.29 Other investigators suggest using immune mediators at narcolepsy onset, such as corticosteroids or immunoglobulins; this has had limited success.9

Hypersomnia Case Revisited

Returning to our case described at the beginning of this article, she demonstrated a compelling history for narcolepsy with cataplexy. She had excessive sleepiness with daytime intrusion of sleep, hypnopompic hallucinations, and cataplexy. Further history revealed both fragmented sleep and episodes of sleep paralysis. Confirmatory CSF hypocretin measurements were unavailable. She was tapered off sertraline and underwent 2 weeks of actigraphy recording with coincident sleep diaries. Upon demonstration of sufficient sleep intake, PSG revealed a total sleep time of 515 minutes without evidence of other sleep disorders. During her MSLT, she had three sleep-onset REM periods between five naps with a mean sleep latency of 3.4 minutes. Urine toxicology revealed no substances (including sertraline). She was started on modafinil and later transitioned to methylphenidate with successful control of daytime sleepiness. Sertraline was restarted for MDD, and her dose was increased to 150 mg daily with control of depressive symptoms and resolution of cataplexy episodes.

Concluding Remarks

The description of sleep disorders and their criteria have changed dramatically in DSM-5 compared with DSM-IV-TR, reflecting the significant progress of sleep medicine. Studies on narcolepsy with cataplexy in particular have advanced our understanding of hypersomnolence disorders, yet significant work still needs to be done.

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Authors

Elliott Kyung Lee, MD, FRCPC, is an Assistant Professor, Institute for Mental Health Research, Department of Psychiatry, University of Ottawa, Faculty of Medicine; and a Sleep Specialist, Royal Ottawa Mental Health Center. Louis Kazaglis, MD, is a Sleep Specialist, Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center.

Address correspondence to Elliott Kyung Lee, MD, FRCPC, Department of Psychiatry, Faculty of Medicine, University of Ottawa, Royal Ottawa Mental Health Center, 1145 Carling Avenue, Ottawa, Ontario, Canada K1Z 7K4; email: elliott.lee@theroyal.ca.

Disclosure: Elliott Kyung Lee discloses a salary from Sleep Strategies. The remaining author has no relevant financial relationships to disclose.

10.3928/00485713-20150106-06

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