74.   Klemens Kaupmann et al., “Specific γ-Hydroxybutyrate-Binding Sites but Loss of Pharmacological Effects of γ-Hydroxybutyrate in GABA-B1-Deficient Mice,” European Journal of Neuroscience 18 (2003): 2722–30.

  75.   S. P. Bessman and W. N. Fishbein, “Gamma-Hydroxybutyrate, a Normal Brain Metabolite,” Nature 200 (December 1963): 1207–8.

  76.   Michel Maitre, Christian Klein, and Ayikoe G. Mensah-Nyagan, “Mechanisms for the Specific Properties of γ-Hydroxybutyrate in Brain,” Medicinal Research Reviews 36 (2016): 363–88.

  77.   Ulrike Leurs et al., “GHB Analogs Confer Neuroprotection Through Specific Interaction with the CaMKIIα Hub Domain,” Proceedings of the National Academy of Sciences 118 (2021): e2108079118.

  78.   Rafael Boscolo-Berto et al., “Narcolepsy and Effectiveness of Gamma-Hydroxybutyrate (GHB): A Systematic Review and Meta-analysis of Randomized Controlled Trials,” Sleep Medicine Reviews 16 (2012): 431–43.

  79.   P. S. van Nieuwenhuijzen, I. S. McGregor, and G. E. Hunt, “The Distribution of Gamma-Hydroxybutyrate-Induced Fos Expression in Rat Brain: Comparison with Baclofen,” Neuroscience 158 (2009): 441–55.

  80.   James K. Walsh et al., “Enhancing Slow Wave Sleep with Sodium Oxybate Reduces the Behavioral and Physiological Impact of Sleep Loss,” Sleep 33 (2010): 1217–25.

  81.   Julie Vienne et al., “Differential Effects of Sodium Oxybate and Baclofen on EEG, Sleep, Neurobehavioral Performance, and Memory,” Sleep 35 (2012): 1071–83.

  82.   Baclofen had undesirable effects on teenagers with narcolepsy in a Taiwanese study, increasing their sleepiness. Yu-Shu Huang and Christian Guilleminault, “Narcolepsy: Action of Two y-Aminobutyric Acid Type B Agonists, Baclofen and Sodium Oxybate,” Pediatric Neurology 41 (2009): 9–16.

  83.   Anne M. Morse, Kristin Kelly-Pieper, and Sanjeev V. Kothare, “Management of Excessive Daytime Sleepiness in Narcolepsy with Baclofen,” Pediatric Neurology 93 (2019): 39–42.

  84.   Sarah Wurts Black et al., “GABA-B Agonism Promotes Sleep and Reduces Cataplexy in Murine Narcolepsy,” Journal of Neuroscience 34 (2014): 6485–94.

  16. BIOMARKERS OF SLEEPINESS—AND IH

    1.   A. Williamson and A. Feyer, “Moderate Sleep Deprivation Produces Impairments in Cognitive and Motor Performance Equivalent to Legally Prescribed Levels of Alcohol Intoxication,” Occupational and Environmental Medicine 57 (October 2000): 649–55.

    2.   In the United States, people diagnosed with narcolepsy or IH do not necessarily have to relinquish their drivers’ licenses; it varies state by state whether diagnoses must be reported to state agencies. Anand Bhat et al., “Drowsy Driving Considerations in Non-Commercial Drivers for the Sleep Physician,” Journal of Clinical Sleep Medicine 15 (2019): 1069–71.

    3.   Fabio Pizza et al., “Car Crashes and Central Disorders of Hypersomnolence: A French Study,” PloS One 10 (2015): e0129386; Pierre Philip et al., “Sleep Disorders and Accidental Risk in a Large Group of Regular Registered Highway Drivers,” Sleep Medicine 11 (2010): 973–79.

    4.   Denise Bijlenga et al., “Comparing Objective Wakefulness and Vigilance Tests to On-the-Road Driving Performance in Narcolepsy and Idiopathic Hypersomnia,” Journal of Sleep Research (2021): e13518.

    5.   Charles A. Czeisler, “Impact of Sleepiness and Sleep Deficiency on Public Health—Utility of Biomarkers,” Journal of Clinical Sleep Medicine 7S (October 2011): S6–S8.

    6.   Janet M. Mullington et al., “Developing Biomarker Arrays Predicting Sleep and Circadian-Couples Risks to Health,” Sleep 39 (April 2016): 727–36.

    7.   Jennifer M. Cori et al., “Eye Blink Parameters to Indicate Drowsiness During Naturalistic Driving in Participants with Obstructive Sleep Apnea: A Pilot Study,” Sleep Health 7 (2021): 644–51.

    8.   Emma Laing et al., “Identifying and Validating Blood mRNA Biomarkers for Acute and Chronic Insufficient Sleep in Humans: A Machine Learning Approach,” Sleep 42 (2019): zsy186.

    9.   David T. Plante, “Hypersomnia in Mood Disorders: A Rapidly Changing Landscape,” Current Sleep Medicine Reports 1 (June 2015): 122–30.

  10.   Alexandros N. Vgontzas et al., “Differences in Nocturnal and Daytime Sleep Between Primary and Psychiatric Hypersomnia: Diagnostic and Treatment Implications,” Psychosomatic Medicine 62 (2000): 220–26.

  11.   David T. Plante, Jesse D. Cook, and Michael L. Prairie, “Multimodal Assessment Increases Objective Identification of Hypersomnolence in Patients Referred for Multiple Sleep Latency Testing,” Journal of Clinical Sleep Medicine 16 (2020): 1241–48.

  12.   David T. Plante et al., “Establishing the Objective Sleep Phenotype in Hypersomnolence Disorder with and Without Comorbid Major Depression,” Sleep 42 (2019): zsz060.

  13.   David T. Plante, “Nocturnal Sleep Architecture in Idiopathic Hypersomnia: A Systematic Review and Meta-analysis,” Sleep Medicine 45 (2018): 17–24.

  14.   Fabio Pizza et al., “Polysomnographic Study of Nocturnal Sleep in Idiopathic Hypersomnia Without Sleep Time,” Journal of Sleep Research 22 (2013): 185–96.

  15.   Kate E. Sprecher et al., “Amyloid Burden Is Associated with Self-Reported Sleep in Nondemented Late Middle-Aged Adults,” Neurobiology of Aging 36 (2015): 2568–76; Eun Y. Joo et al., “Analysis of Cortical Thickness in Narcolepsy Patients with Cataplexy,” Sleep 34 (October 2011): 1357–64.

  16.   Stephanie G. Jones et al., “Regional Reductions in Sleep Electroencephalography Power in Obstructive Sleep Apnea: A High-Density EEG Study,” Sleep 37 (2014): 399–407.

  17.   Another option could be experimental magnetic devices. Marcello Massimini et al., “Triggering Sleep Slow Waves by Transcranial Magnetic Stimulation,” Proceedings of the National Academy of Sciences 104 (2007): 8496–501.

  18.   U.S. National Library of Medicine, “Neurophysiologic Correlates of Hypersomnia,” https://www.clinicaltrials.gov/ct2/show/NCT01719315. Acoustic experiments were also proposed in Plante’s National Institute for Neurological Disorders and Stroke grant application.

  19.   James K. Walsh et al., “Slow Wave Sleep Enhancement with Gaboxadol Reduces Daytime Sleepiness During Sleep Restriction,” Sleep 31 (2008): 659–72.

  20.   Ransdell Pierson, “Merck, Lundbeck Scrap Insomnia Drug After Trials,” Reuters, March 28, 2007.

  21.   Thien T. Dang-Vu et al. “Cerebral Correlates of Delta Waves During Non-REM Sleep Revisited,” Neuroimage 28 (2005): 14–21.

  22.   Eun Y. Joo et al., “Cerebral Perfusion Abnormality in Narcolepsy with Cataplexy,” Neuroimage 28 (November 2005): 410–16.

  23.   Thien T. Dang-Vu et al., “Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism,” PLoS One 10 (2015): e0133474.

  24.   Robert A. Veselis et al., “Midazolam Changes Cerebral Blood Flow in Discrete Brain Regions: An H2(15)O Positron Emission Tomography Study,” Anesthesiology 87 (1997): 1106–17.

  25.   Florence B. Pomares et al., “Beyond Sleepy: Structural and Functional Changes of the Default-Mode Network in Idiopathic Hypersomnia,” Sleep 42 (2019): zsz156.

  26.   Lynn M. Trotti, “Waking Up Is the Hardest Thing I Do All Day: Sleep Inertia and Sleep Drunkenness,” Sleep Medicine Reviews 35 (October 2017): 76–84.

  27.   Carlos H. Schenck, Erin C. Golden, and Richard P. Millman, “Treatment of Severe Morning Sleep Inertia with Bedtime Long-Acting Bupropion and/or Long-Acting Methylphenidate in a Series of 4 Patients,” Journal of Clinical Sleep Medicine 17 (2021): 653–57.

  28.   Raphael Vallat et al., “Hard to Wake Up? The Cerebral Correlates of Sleep Inertia Assessed Using Combined Behavioral, EEG, and fMRI measures,” Neuroimage 184 (2019): 266–78.

  29.   Patricia Tassi et al., “EEG Spectral Power and Cognitive Performance During Sleep Inertia: The Effect of Normal Sleep Duration and Partial Sleep Deprivation,” Physiology & Behavior 87 (2006): 177–84.

  30.   Thomas J. Balkin et al., “The Process of Awakening: A PET Study of Regional Brain Activity Patterns Mediating the Re-establishment of Alertness and Consciousness,” Brain 125 (2002): 2308–19.

  31.   Bedřich Roth et al., “Neurological, Psychological, and Polygraphic Findings in Sleep Drunkenness,” Schweizer Archiv für Neurologie, Neurochirurgie und Psychiatrie 129 (1981): 209–22.

  32.   The Emory IH group fit ICSD-3 sleep latency criteria, but only a few reported long sleep periods. The experiments focusing on sleep drunkenness had not yet been analyzed.

  33.   Yves Dauvilliers et al., “18F-FDG-Positron Emission Tomography Evidence for Cerebral Hypermetabolism in the Awake State in Narcolepsy and Idiopathic Hypersomnia,” Frontiers in Neurology 8 (2017): 350.

  34.   Rachel Danzig et al., “The Wrist Is Not the Brain: Estimation of Sleep by Clinical and Consumer Wearable Actigraphy Devices Is Impacted by Multiple Patient- and Device-Specific Factors,” Journal of Sleep Research 29 (2020): e12926.

  35.   Jesse D. Cook, Michael L. Prairie, and David T. Plante, “Utility of the Fitbit Flex to Evaluate Sleep in Major Depressive Disorder: A Comparison Against Polysomnography and Wrist-Worn Actigraphy,” Journal of Affective Disorders 217 (2017): 299–305. Jesse D. Cook, Michael L. Prairie, and David T. Plante, “Ability of the Multisensory Jawbone UP3 to Quantify and Classify Sleep in Patients with Suspected Central Disorders of Hypersomnolence: A Comparison Against Polysomnography and Actigraphy,” Journal of Clinical Sleep Medicine 14 (2018): 841–48.

  36.   Anniina Alakujala et al., “Accuracy of Actigraphy Compared to Concomitant Ambulatory Polysomnography in Narcolepsy and Other Sleep Disorders,” Frontiers in Neurology 12 (2021): 629709.

  37.   Michael T. Smith et al., “Use of Actigraphy for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An American Academy of Sleep Medicine Clinical Practice Guideline,” Journal of Clinical Sleep Medicine 14 (2018): 1231–37.

  38.   Jenny Gold, “The Sleep Apnea Business Is Booming, and Insurers Aren’t Happy,” NPR Morning Edition, January 16, 2012.

  39.   Massimiliano de Zambotti et al., “Sensors Capabilities, Performance, and Use of Consumer Sleep Technology,” Sleep Medicine Clinics 15 (2020): 1–30.

  40.   Elisa Evangelista et al., “Alternative Diagnostic Criteria for Idiopathic Hypersomnia: A 32-Hour Protocol,” Annals of Neurology 83 (2018): 235–47.

  41.   Elisa Evangelista et al., “Sleep Inertia Measurement with the Psychomotor Vigilance Task in Idiopathic Hypersomnia,” Sleep (August 2021): zsab220.

  17. THE FDA OPENS A DOOR

    1.   Alyssa Cairns and Richard Bogan, “To Withhold or Not Withhold? Use of Psychiatric Medications on MSLT Outcomes in 1033 Patients,” Sleep 42S (2019): A250–51.

    2.   Lynn M. Trotti, Beth A. Staab, and David B. Rye, “Test-Retest Reliability of the Multiple Sleep Latency Test in Narcolepsy Without Cataplexy and Idiopathic Hypersomnia,” Journal of Clinical Sleep Medicine 9 (2013): 789–95; Regis Lopez et al., “Test-Retest Reliability of the Multiple Sleep Latency Test in Central Disorders of Hypersomnolence,” Sleep 40 (2017): zsx164; Chad Ruoff et al., “The MSLT Is Repeatable in Narcolepsy Type 1 but Not Narcolepsy Type 2: A Retrospective Patient Study,” Journal of Clinical Sleep Medicine 14 (2018): 65–74.

    3.   Rolf Fronczek et al., “To Split or to Lump? Classifying the Central Disorders of Hypersomnolence,” Sleep 43 (2020): zsaa044.

    4.   Lei Chen et al., “The Familial Risk and HLA Susceptibility Among Narcolepsy Patients in Hong Kong Chinese,” Sleep 30 (2007): 851–58.

    5.   Gert J. Lammers et al., “Diagnosis of Central Disorders of Hypersomnolence: A Reappraisal by European Experts,” Sleep Medicine Reviews 50 (2020): 101306.

    6.   Kiran Maski, Emmanuel Mignot, and Thomas E. Scammell, “Commentary on Lammers et al.,” Sleep Medicine Reviews 52 (2020): 101327.

    7.   Gert J. Lammers, “Diagnosing Hypersomnia Differently: A European Proposal,” Hypersomnia Foundation, YouTube video posted May 19, 2021, https://www.youtube.com/watch?v=BHEKcbJQ7P4.

    8.   Michel Billiard, “Diagnosis of Narcolepsy and Idiopathic Hypersomnia. An Update Based on the International Classification of Sleep Disorders, 2nd Edition,” Sleep Medicine Reviews 11 (2007): 377–88.

    9.   Emily Singer, “Diagnosis: Redefining Autism,” Nature 491 (2012): S12–13; Karen Brown, “ ‘Schizophrenia’ Still Carries a Stigma. Will Changing the Name Help?,” New York Times, December 20, 2021.

  10.   Risperidone and aripiprazole were FDA approved for irritability associated with autism, but irritability is not considered a core symptom of autism. Sheena LeClerc and Deidra Easley, “Pharmacological Therapies for Autism Spectrum Disorder: A Review,” Pharmacy and Therapeutics 40 (2015): 389–R397.

  11.   Bedřich Roth, Narcolepsy and Hypersomnia (Basel: Karger, 1980), 159.

  12.   Francesco P. Cappuccio et al., “Sleep Duration and All-Cause Mortality: A Systematic Review and Meta-analysis of Prospective Studies,” Sleep 33 (2010): 585–92.

  13.   John Acquavella et al., “Prevalence of Narcolepsy and Other Sleep Disorders and Frequency of Diagnostic Tests from 2013–2016 in Insured Patients Actively Seeking Care,” Journal of Clinical Sleep Medicine 16 (2020): 1255–63.

  14.   Yves Dauvilliers et al., “Safety and Efficacy of Lower-Sodium Oxybate in Adults with Idiopathic Hypersomnia: A Phase 3, Placebo-Controlled, Double-Blind, Randomised Withdrawal Study,” Lancet Neurology 21 (2022): 53–65.

  15.   S. Nassir Ghaemi and Harry P. Selker, “Maintenance Efficacy Designs in Psychiatry: Randomized Discontinuation Trials—Enriched but Not Better,” Journal of Clinical and Translational Science 1 (2017): 198–204; Lynn Marie Trotti, “Idiopathic Hypersomnia: Does First to Approval Mean First-Line Treatment,” Lancet Neurology 21 (2022): 25–26.

  16.   Takeda Pharmaceutical Company press release, “Takeda Provides Update on TAK-994 Clinical Program,” October 5, 2021.

  17.   Press releases from Harmony Biosciences, “Harmony Biosciences Initiates a Phase 2 Clinical Trial in Myotonic Dystrophy,” June 29, 2021; “Harmony Biosciences Announces Plans to Initiate Phase 3 Clinical Trial for Treatment of Idiopathic Hypersomnia,” December 1, 2021.

  18.   Jazz Pharmaceuticals, Sunosi investor update from July 2, 2019, downloaded from Jazz website, p. 33.

  19.   Rachel Sachs, “The FDA’s Approval of Aduhelm: Potential Implications Across a Wide Range of Health Policy Issues and Stakeholders,” Health Affairs Forefront, 2021, https://www.healthaffairs.org/do/10.1377/forefront.20210609.921363.

  20.   Through the Freedom of Information Act, I have requested FDA clinical review documents for Xywav and IH, which are available for other approved medications, such as solriamfetol and pitolisant.

  21.   Ragy Saad et al., “Clinical Presentation Prior to Idiopathic Hypersomnia Diagnosis Among US Adults: A Retrospective, Real-World Claims Analysis,” Sleep 44S (2021): A196.

  22.   U.S. Food and Drug Administration, “FDA Drug Safety Communication: Warning Against Use of Xyrem (Sodium Oxybate) with Alcohol or Drugs Causing Respiratory Depression,” December 17, 2012.

  23.   Ruzica Kovacević-Ristanović and Tomasz J. Kuźniar, “Use of Sodium Oxybate (Xyrem) in Patients with Dual Diagnosis of Narcolepsy and Sleep Apnea,” Sleep Medicine 11 (2010): 5–6.

  24.   The Times article emphasized GHB’s lurid past, prompting a backlash from the IH community online. Virginia Hughes, “F.D.A. Approves GHB, a ‘Date Rape’ Drug, for Rare Sleeping Disorder,” New York Times, August 12, 2021.

  25.   Jazz Pharmaceuticals “Sleep Counts” website, viewed 2021, https://www.sleepcountshcp.com/patient-profiles-stories-videos.

  26.   Ragy Saad et al., “Utilization of Diagnostic Sleep Testing Prior to Idiopathic Hypersomnia Diagnosis Among US Adults: A Real-World Claims Analysis,” Sleep 44S (2021): A197.

  27.   Thomas Roth et al., “Characteristics of Subjects Excluded from an Idiopathic Hypersomnia Randomized Clinical Trial (ARISE2),” Sleep Medicine 64S (2019): S327–28.

  28.   Sharon Begley, “ ‘A Feature Not a Bug’: George Church Ascribes His Visionary Ideas to Narcolepsy,” STAT, June 8, 2017.

  29.   Judy Singer, NeuroDiversity: The Birth of an Idea (2017).

  30.   Celia Lacaux et al., “Increased Creative Thinking in Narcolepsy,” Brain 142 (2019): 1988–99.

  31.   Michelle Emrich, “Broken by IH,” https://www.youtube.com/watch?v=Ww_6LfS4dFc.

  32.   Jason C. Ong et al., “Developing a Cognitive Behavioral Therapy for Hypersomnia Using Telehealth: A Feasibility Study,” Journal of Clinical Sleep Medicine 16 (2020): 2047–62.