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Medication

Medication Summary

In August 2021, the FDA approved, calcium/magnesium/potassium/sodium oxybates (Xywav), the first drug indicated for idiopathic hypersomnia. It is a CNS depressant that contains salts of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter GABA. It may be administered as either a once or twice nightly regimen.

Daytime stimulants

Patients often require drug therapy to treat daytime hypersomnolence. Prior to initiating therapy with stimulants, clearly establish a diagnosis and consider potential for abuse.^{[83, 75]}

Modafinil, a wake-promoting agent, is approved for treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), and shift-work sleep disorder (SWSD).^{[88, 84]}The studies have shown significant benefits on various objective measures and subjective estimates of excessive sleepiness.

The clinical efficacy of modafinil, combined with its improved safety over CNS stimulants, has made it the most prescribed medication for the treatment of excessive sleepiness associated with narcolepsy. Unlike many other medications used for excessive sleepiness, modafinil is not known to be abused. The most common adverse event reported in clinical studies was headaches; most were transient and mild to moderate in severity. Modafinil also has the potential for interactions with other drugs metabolized via cytochrome P450 enzyme pathways.

For Kleine-Levin syndrome, somnolence can decrease with stimulants (mainly amphetamines), while neuroleptics and antidepressants are of poor benefit. Lithium, rather than carbamazepine or other antiepileptics, was found to have a higher success rate for stopping relapses.^[89]

Class Summary

Mixture of calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate (gamma-hydroxybutyrate [GHB]). GHB is an endogenous compound and metabolite of the neurotransmitter GABA.

Calcium/magnesium/potassium/sodium oxybates (Xywav)

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Indicated for adults with idiopathic hypersomnia.

Class Summary

These agents have wake-promoting activities.

Modafinil (Provigil)

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Modafinil, (1:1 racemic mixture of R- and S-modafinil) improves wakefulness, though the mechanism of action remains unclear. It may act at the dopamine receptor (DAT), inhibiting dopamine reuptake and may exert stimulant effects by decreasing GABA-medicated neurotransmission. It has wake-promoting actions similar to those of sympathomimetic agents, though no direct action on dopamine receptors themselves; wakefulness is not attenuated by known dopamine antagonists.

Armodafinil (Nuvigil)

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Armodafinil is an R-enantiomer of modafinil (mixture of R- and S-enantiomers). It elicits wake-promoting actions similar to those of sympathomimetic agents, although its pharmacologic profile is not identical to sympathomimetic amines and has no direct action on dopamine receptors themselves. Wakefulness is not attenuated by known dopamine antagonists. It may act at the dopamine receptor (DAT), inhibiting dopamine reuptake and may exert stimulant effects by decreasing GABA-medicated neurotransmission. It is not a direct- or indirect-acting dopamine receptor agonist. Armodafinil is indicated for the improvement of wakefulness in individuals with excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), or shift-work sleep disorder.

Methylphenidate (Ritalin, Daytrana, Methylin, Concerta)

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Methylphenidate is used for symptomatic management of primary hypersomnolence whenever the patient needs to be alert or engages in activities in which hypersomnolence may be hazardous. The drug blocks the reuptake mechanism of dopaminergic neurons. Methylphenidate stimulates the cerebral cortex and subcortical structures.

Dextroamphetamine (Procentra, Dexedrine, Zenzedi)

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This agent increases the amount of circulating dopamine and norepinephrine in the cerebral cortex by blocking the reuptake of norepinephrine or dopamine from the synapse.

Dextroamphetamine and amphetamine mixtures (Mydayis, Adderall XR)

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This agent produces CNS and respiratory stimulation. The CNS effect may occur in the cerebral cortex and reticular activating system. Dextroamphetamine-amphetamine mixture may have a direct effect on alpha- and beta-receptor sites in the peripheral system and may also release stores of norepinephrine in adrenergic nerve terminals. The mixture contains various salts of amphetamine and dextroamphetamine. It is available as 5-, 7.5-, 10-, 12.5-, 15-, 20-, and 30mg scored tablets.

Amphetamine (Evekeo)

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Amphetamines are noncatecholamine sympathomimetic amines that promote release of catecholamines from their storage sites in the presynaptic nerve terminals. Amphetamine 1:1 racemic mixture of dextroamphetamine and levoamphetamine (immediate release only) has an FDA indication for promoting wakefulness in narcolepsy.

Questions

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Media Gallery

Primary hypersomnia. Polysomnographic study demonstrates apnea (absence of carbon dioxide fluctuation indicating no flow), chest wall paradox, abrupt increase in tidal volume at the end of apnea, and oxygen desaturation. All of these features are consistent with obstructive sleep apnea.
Primary hypersomnia. In contrast to obstructive sleep apnea, mixed apnea shows absence of respiratory efforts in the first segment of the apnea.
Primary hypersomnia. Periodic limb movements show intermittent leg electromyogram activity accompanied by electroencephalogram arousals.

of 3

ISCD-3 Central Disorders of Hypersomnolence

ISCD-3 Central Disorders of Hypersomnolence

Primary

Secondary

Narcolepsy type 1 (NT1)

Narcolepsy type 2 (NT2)

Hypersomnia due to a medical condition

Hypersomnia due to a psychiatric condition

Idiopathic hypersomnia (IH)

Hypersomnia due to a drug or substance

Kleine-Levin syndrome (KLS)

Insufficient sleep syndrome (ISS)

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Author

Adrian Preda, MD, DFAPA Professor of Clinical Psychiatry and Human Behavior, Department of Psychiatry and Human Behavior, University of California, Irvine, School of Medicine

Adrian Preda, MD, DFAPA is a member of the following medical societies: American Association for the Advancement of Science, American Psychiatric Association, International College of Neuropsychopharmacology, International Congress of Schizophrenia Research, Schizophrenia International Research Society, Society of Biological Psychiatry

Disclosure: Nothing to disclose.

Coauthor(s)

David R Bowman, MD Psychiatrist, Deputy Chief, Joint Behavioral Health Clinic, Multi-Disciplinary Outpatient Clinic, Medical Review Officer, Clinical Practice Guidelines Champion, External Behavioral Health Consultant, Department of Behavioral Health, Moncrief Army Health Clinic

David R Bowman, MD is a member of the following medical societies: American Psychiatric Association, American Society for Adolescent Psychiatry, American Society of Addiction Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Ana Hategan, MD, FRCPC Associate Clinical Professor, Department of Psychiatry and Behavioral Neurosciences, Division of Geriatric Psychiatry, McMaster University School of Medicine; Geriatric Psychiatrist, St Joseph's Health Care Hamilton, Canada

Ana Hategan, MD, FRCPC is a member of the following medical societies: Canadian Academy of Geriatric Psychiatry, Canadian Coalition for Seniors' Mental Health, Canadian Psychiatric Association, International Psychogeriatric Association, Ontario Medical Association, Royal College of Physicians and Surgeons of Canada

Disclosure: Book royalties and/or honoraria for articles from American Psychiatric Publishing, Springer, and Current Psychiatry.

Acknowledgements

Jennifer S Morse, MD Associate Medical Director, Optum Health

Jennifer S Morse, MD is a member of the following medical societies: Academy of Psychosomatic Medicine, Aerospace Medical Association, and American Psychiatric Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Primary Hypersomnia Medication

Medication Summary

CNS Depressants

Class Summary

Calcium/magnesium/potassium/sodium oxybates (Xywav)

Calcium/magnesium/potassium/sodium oxybates (Xywav)

Stimulants