Comorbidity of Sleep Disorders and Mortality: Excessive Sleepiness & Hypersomnolence Issues

Scope of the Meeting


  1. To understand how the presence of hypersomnolence might complicate interventions and treatments of mental disorders.
  2. To recognize the importance of sleep disorders in devising public health interventions.
  3. To understand the place of Hypersomnolence as a public mental health issue in terms of predictor of a more serious illness and/or increased mortality risk in hypersomnolent individuals.


Saturday, August 31rst, 2013

08:30 - 08:40 Maurice Ohayon, MD, DSc, PhD, Chair
Welcome / Overview of the meeting
08:40 - 09:15 Laura Roberts, MD, MA
Hypersomnolence and Comorbidity in the General Population
09:15 - 10:00 Edward Bixler, PhD
Comorbidity of Sleep Disorders Penn State Child & Adult Cohorts
10:00 - 10:15 Discussion
Sleeping Too much:Are Mental Disorders a risk factor?
Medical Disorders and relationship with Hypersomnolence and sleeping
10:15 - 10:30 Break
10:30 - 11:15 Michael Vitiello, PhD
Relationship of Insomnia Symptoms and Naps with Co-Morbid Illnesses in Older Adults
11:15 - 12:00 Victor Rosenfeld, MD
Sleep Disorder Spectrum in FMS
12:00 - 12:15 Discussion
12:15 - 13:30 Lunch
12:30 - 13:30 Lunch
13:30 - 14:15 Todd Swick, MD
Comorbidities of Hypersomnia: Chicken or Egg?
14:15 - 15:00 Diane Guinta, PhD
Narcolepsy Mortality from an Insurance Database
15:00 - 15:15 Discussion
15:15 - 15:30 Break
15:30 - 16:15 Thomas Kilduff, Ph.D
Cortical nNOS/NK1 Neurons Link Homeostatic Sleep Drive to EEG Slow Wave Activity
16:15 - 17:00 Plazzi Giuseppe, MD, PhD
Narcolepsy and comorbid conditions in children
17:00 - 17:45 Alan K. Louie, MD
Barriers to Training in Public Mental Health
17:45 - 18:00 Maurice Ohayon, MD, DSc, PhD, Chair
General Discussion
Place of Hypersomnolence and Narcolepsy in the DSM-5
Future directions of Research


Comorbidity of Sleep Disorders in the General Population (Penn State Child & Adult Cohorts)
Edward Bixler, PhD
Based on available representative population data sleep disturbance appears to have a strong moderating effect on health including mortality. For example EDS is inversely associated with age, strongly associated with depression, obesity, cytokines and weakly associated with AHI. With SDB the risk for blood pressure also appears to be age related, which is consistent with its association with severity and mortality, and AHI is considered by some as a moderating variable for the metabolic syndrome. Finally, the chronic insomnia complaint combined with reduced sleep duration is associated with increased medical risk including mortality

Narcolepsy Mortality from an Insurance Database.
Diane Guinta, PhD
Data from a large insurance claims database was linked to the US Social Security Death Master File to study mortality in narcolepsy.
An elevated standardized mortality ratio for narcolepsy compared with the general population was observed.

Depression, Pain and Comorbidity in the General Population
Maurice Ohayon, MD, DSc, PhD
Sleep disturbances are common in individuals experiencing chronic pain. Subjective measures of sleep in various chronic pain conditions mostly demonstrate a high number of complaints of disrupted and unrefreshing sleep. Similarly, pain is very common in individuals with depression as are also sleep disturbances.
This cross-sectional telephone study involved 15,945 individuals representative of the American adult general population (≥ 18 years) living in 15 states. Participants were interviewed on life and sleeping habits; health; medication consumption, medical conditions (ICD-10), sleep disorders (ICSD) and mental disorders (DSM-IV-TR) using Sleep-EVAL.
Overall, 32.6% of the sample reported sleep disturbances (3 nights/week for at least 3 months; 34.9% reported chronic pain (>=3 months) and 5.7% a Major Depressive Disorder (MDD).
The triple association, MDD, chronic pain and sleep disturbances was observed in 2.4% of the sample; MDD occurred without pain or sleep disturbances in only 0.9% of the sample. Individuals with the triple association had more severe impact on their daily life (daily activities, social and family activities) and were twice more likely to report deteriorated QOL than individuals with MDD alone or MDD with either pain or sleep disturbances.
Presence of pain complicated the treatment of MDD. However, negative impacts on functioning are maximal when sleep disturbances are also present.

Hypersomnolence and Comorbidity in the General Population
Maurice Ohayon, MD, DSc, PhD
Hypersomnolence, often called excessive sleepiness or hypersomnia, has lacked of uniform definition. This population-based study examined the association between excessive quantity of sleep (EQS), medical and psychiatric comorbidities and consequences on daily functioning.
The study involved a representative sample of 19,136 non-institutionalized individuals living in the US, aged ≥18 (participation rate: 83.2%). Sleep-EVAL questionnaire included sleeping habits; health; sleep, mental and organic disorders (DSM-IV-TR, ICSD-II, ICD-10).
Sleeping ≥9 hours per 24-hour period was reported by 8.4% (8.0%-8.8%) of participants; EQS (with distress/impairment) was observed in 1.6% (1.4%-1.8%) of the sample.
The likelihood of EQS was 3-12 times higher among individuals with a mood disorder. EQS individuals were 2-4 times more likely to report poor quality of life than non-EQS individuals as well as interference with socio-professional activities and relationships. Between 33% and 66% of EQS individuals perceived it as a major problem, only 6.3% to 27.5% of them reported having sought medical attention.
EQS is widespread in the general population, co-occurring with a broad spectrum of sleep, medical, neurologic and psychiatric disorders. Therefore, physicians must recognize EQS as a mixed clinical entity indicating careful assessment and specific treatment planning.

Food, nutrients and non-nutrient bioactive compounds in health Promotion. Example Plant Extract (Pycnogenol) Diabetes Risk Reduction
Ronald Ross Watson, PhD
Polyphenols in Pycnogenol, an extract of pine bark, were tested to reduce blood pressure, glucose and other risk factors in type 2 diabetics being treated with conventional anti-blood pressure drugs. Pycnogenol has been studied in 100+ small clinical trials with emphasis on diabetes and hypertension. Dr. Watson also showed that it prevented and treated congestive heart failure in mice, suggesting a role for a major human disease.
Therefore type 2 diabetics were given Pycnogenol, a patented pine bark extract at 150 mg/day for 12 weeks and studied for changes in their risk factors for heart disease and progression of diabetes. Diabetes affects about 8% of Americans with pre-diabetes more common and whose progression can be slowed. Hypertension and cardiovascular disease are major complications of progressing diabetes. Enzymatically Pycnogenol slows glucose absorption.
We found that it lowered blood glucose levels. Also the dietary supplement lowered nitric oxide production and resulting arterial constriction, a risk factor for CVD. Pycnogenol lowered LDL-cholesterol. It was multifunctional when compared to pharmaceutical drugs routinely provided diabetics with cardiovascular complications. Looking at costs per unit benefit using changes in HgAlC Pycnogenol was cheaper than pharmaceutical drugs.
Therefore Pycnogenol shows promise as a supplement to traditional diabetes treatments and is competitively cost-effective as compared to pharmaceutical regimens.

Sleep Disorder Spectrum in FMS
Victor Rosenfeld, MD
Fibromyalgia (FMS) is the most common widespread pain disorder in the world. It is present in 2-8% of the population. Originally described by a Neurologist in 1890 as Neurasthenia, it was associated with fatigue and sleep complaints. Recent research oriented criteria include Sleep and Fatigue co-morbidities, and a recent survey of FMS patients ranked sleep and fatigue complaints as more prominent than pain complaints.
Sleep complaints in FMS include Hypersomnia, Insomnia, Sleep Related Breathing Disorders, Sleep Related Movement Disorders, and Non-restorative Sleep. This lecture will discuss the identification and testing of Sleep Disorders in FMS.

Barriers to Training in Public Mental Health
Alan K Louie, MD
A significant gap exists between the number of people suffering from psychiatric disorders and the number who actually receive treatment. This mismatch is also evident even when looking only at those with serious mental illness, who are often part of the public mental health system.
This situation is and will be potentially exacerbated by a deficit of psychiatrists in the United States. Workforce projects suggest a shortage of psychiatrists, especially of child and adolescent psychiatrists. This may be even worse for the public sector, given the lack of interest in and preparation for working in this sector. Possible solutions to address this are discussed.

Narcolepsy and H1N1 story: French experience
Yves Dauvilliers, MD, PhD
In 2010, researchers reported a cluster of new Narcolepsy cases in France, Sweden and Finland, mainly among children and adolescents, following the influenza H1N1 infection or vaccination.
Epidemiological studies in Sweden, Finland, Norway, UK and France have shown a 4-13 fold increased risk of developing childhood Narcolepsy following Pandemrix®, the only used brand of pandemic 2009 H1N1 influenza vaccine in these countries (only 1 of 16,000 vaccinated children developed Narcolepsy, however). In 2011, it was reported that the incidence of childhood Narcolepsy increased several fold in China following the H1N1 winter flu pandemia.
These results bolster the claim that Narcolepsy, an autoimmune disease caused by hypocretin cell loss, could be triggered by H1N1 vaccination or infection.

Relationship of Insomnia Symptoms and Naps with Co-Morbid Illnesses in Older Adults
Michael V. Vitiello, PhD
Sleep-related complaints and regular napping behavior both increase with advancing age.
Using two samples of older adults we will describe the frequency of sleep-related complaints, regular napping and co-morbid illnesses and their associations in this population.
Examination of the VITAL cohort of 55,000+ older (50-76 yrs) community-dwelling adults showed: a high prevalence of nighttime sleep complaints, which significantly increased with age, a high prevalence of daytime sleep-related complaints, which significantly decreased with age, and significant associations between both overall medical burden and individual illnesses, particular depression, with both daytime and nighttime sleep-related complaints. Examination of the National Sleep Foundation 2003 Sleep in America Poll cohort of 1,417 older (55-84 yrs) community-dwelling adults showed; regular napping behavior significantly increased with age, and regular napping was significantly associated with excessive daytime sleepiness (EDS), depression, pain/medical burden and nocturia.

Comorbidities of Hypersomnia: Chicken or Egg?
Todd J. Swick, MD
The classification of central hypersomnias is presented using the latest DSM-V and proposed ICSD-3 nosology. A review of the known and suspected comorbidities associated with the central hypersomnias is presented. A review of the psychosocial signs and symptoms in adults and children is covered. Endocrine/metabolic dysregulation, psychiatric and cognitive abnormalities will be discussed.
Results of five pivotal studies including:
- 1) the heath related QOL in drug naïve patients with narcolepsy/cataplexy, narcolepsy without cataplexy and idiopathic hypersomnia by Ozaki,
- 2) Depression: relationships to sleep paralysis and other sleep disturbances in a community sample by Szklo-Coxe,
- 3) Comorbidity and mortality of narcolepsy: A controlled retro-and prospective national study by Jennum,
- 4) Telephone interviews using Sleep-Eval system by Ohayon and
- 5) Burden of Narcolepsy Disease Study by Black will be reviewed.
The issues of symptom onset, delays in diagnosis and its impact on the comorbidities described above will be discussed.

Obstructive Sleep Apnea: Comorbid Conditions & Health Care Utilization
Max Hirshkowitz, PhD, DABSM
Obstructive Sleep Apnea (OSA) is a sleep-related breathing disorder that involves large airway collapse, partial collapse, or both for 10s, or more. These sleep-related respiratory events provoke blood oxygen level decreases of 3-4% or more and/or awakenings or brief CNS arousals.
Direct consequences include:
- sleepiness;
- accidents (including motor vehicle);
- impaired coping; hypertension;
- heart disease; stroke; and
- decrease quality of life.
Secondary consequences include exacerbations of COPD, heart disease, and mood disorder.
We used the VHA database to determine prevalence, explore comorbid conditions, and assess health care utilization in patients diagnosed with OSA. The Department of Veterans Affairs runs the largest US health care system (7+ million beneficiaries). Since early ‘90s there have been attempts to develop centralized medical information systems. We searched two resources: (1) The Outpatient Care File that was started in 1997 and contains records of all outpatient visits and (2) The Patient Treatment File that was started in 1992 and that contains records of all inpatient admissions. Both of these databases use ICD9 and CPT codes.
We found the highest prevalence at ages 35-64; the incidence was increasing steadily; and the overall prevalence was 2.9%. To estimate actual prevalence we used Young (1997) data showing 83% of moderate to severe OSA is undiagnosed. Extrapolation would indicate an estimated VA OSA prevalence ay 11.7%.
We found higher than control percentages of the following comorbid conditions: Heart failure, obesity, diabetes, anxiety disorders, depression, and stroke. Patients with OSA consistently use the health care system more than other patients; however, the pattern of usage differs. For medical problems the OSA diagnosis appears to be a watershed marker. In contrast to previous reports, health care utilization does not decline in this older, predominantly male population

Ethical Considerations in Serious Illness Research
Laura W. Roberts, MD, MA
Human research is founded on the ethical principles of Respect for Persons, Beneficence, and Justice. Ethical controversy has surrounded the conduct of human studies involving potentially vulnerable research volunteers, including people living with serious physical and mental illnesses. Scientific neglect of diseases that cause premature mortality and disability such as HIV, cancer, depression, and schizophrenia is itself unethical.
Regulatory issues and professional practices to assure the ethical soundness of human studies will be characterized. Key findings from the emerging field of evidence based ethics will be provided. Data from a series of survey and structured-interview studies funded by the NIMH, NIDA, and NHGRI will be presented clarifying the perspectives of clinical research protocol participants and of investigators regarding ethically-important aspects of human research. Also presented will be videotaped footage of protocol participants with serious illness commenting on the ethical safeguard of informed consent and their experiences in clinical research protocols.

How Can We Improve Public Policies that Affect People Who have Addictive and Psychiatric Disorders?
Keith Humphreys, PhD
Scientists in psychiatry tends to focus on how their research findings might translate to clinical care, but it is equally important to consider how they might influence laws and regulations that affect the lives of people who have addictive and psychiatric disorders. These includes laws about health care, health insurance and criminal justice.
This presentation by a psychiatry professor who has worked extensive in public policy circles describes how researchers can make an impact on public policy. As examples, the presentation will highlight the role of research and clinical experience in influencing the shape of the 2008 Mental Health Parity Act and the 2010 Affordable Care Act.

Obesity Genetics: How Much of a Role does Genetics Play in Predicting
Jerome Yesavage, MD
As individuals age they are subject to numerous factors that negatively impact cognitive function. The most well-known factors are the development of Alzheimer's disease (AD) and its precursor Mild Cognitive Impairment (MCI), which have been linked to genetics factors such as the apolipoprotein E4 (APOE4) genotype.
The question this work addresses is whether there are genetic factors linked to obesity, that might also affect cognition in older adults without AD and MCI.
Subjects were older adults participating in studies in the Aging Clinical Research Center at Stanford. Subjects covered a broad cross-section of society. Average age was 68 years old. All were tested on:
Rey Auditory Verbal Learning Task (RAVLT).
Detailed health questionnaires.
Whole genome scan using Illumina technology.
A subset were assessed for sleep apnea.
Cognitive decline in "young" older adults is linked to cardiovascular risk factors. Genetic factors, though measurable, appear to play a relatively smaller role in the development of obesity.
Direct links between obesity and cognitive decline are also small, but probably obesity has effects on cognition due to its linkage to hypertension, diabetes and sleep apnea.

Cortical nNOS/NK1 Neurons Link Homeostatic Sleep Drive to EEG Slow Wave Activity
Thomas S. Kilduff, PhD
Although the neural circuitry underlying homeostatic sleep regulation is little understood, cortical nNOS/NK1 neurons have been proposed to be involved in this physiological process. By systematically manipulating the durations of sleep deprivation and subsequent recovery sleep, we show that activation of cortical nNOS/NK1 neurons is directly related to NREM sleep time, NREM bout duration, and EEG delta power during NREM sleep, an index of pre-existing homeostatic sleep drive. Conversely, nNOS knockout mice show reduced NREM sleep time, shorter NREM bouts, and decreased power in the low delta range during NREM sleep, despite constitutively elevated sleep drive. Cortical NK1 neurons are still activated in response to sleep deprivation in these mice but, in the absence of nNOS, they are unable to upregulate NREM delta power appropriately. These findings support the hypothesis that cortical nNOS/NK1 neurons translate homeostatic sleep drive into upregulation of NREM delta power through an NO-dependent mechanism.


Sleepiness at the wheel
MA Quera Salva, MD, PhD
Sleepiness at the wheel is a major international public health issue, as it contributes substantially to the heavy burden of traffic-related morbidity and mortality [1, 2]. Although highways are associated with fewer accidents per kilometer than are other roads, driver sleepiness has been estimated to cause 37% of fatal accidents on the highway network in France [3] and it has been suggested that the monotonous nature of highway driving decreases the ability of drivers to react to unpredictable events [8].
Despite major improvements in vehicle design, legislation concerning alcohol use, and national road-safety campaigns, accidents continue to occur. Sleepiness at the wheel is a major contributor to motor vehicle accidents.
Efforts to reduce the monotony of long drives include the creation of billboards and rest areas. In France from 2001 to 2011, the number of automobile accidents overall decreased gradually, by nearly 50% [5]. However, there were still 3970 road deaths in 2011.
We recently conducted a prospective observational study in the freeway including 3051 drivers selected at random by highway-patrol officers (article in press in Sleep Medicine). The study was designed to assess drivers’ behavior and risk factors for sleepiness. Information on sleepiness and subjective sleep complaints during the past 3 months by completing the Epworth Sleepiness Scale, the Basic Nordic Sleep Questionnaire and a 10-cm visual analogue scale (VAS) for subjective sleepiness at the time of the interview (0 very sleepy; 10, not at all sleepy). Finally, the interviewers determined whether the participants had experienced any of the following: severe sleepiness during the current trip leading to a Near Miss Accident (NMSA), (yes/no); NMSA in the past year (yes/no); and sleepiness-related accident in the past year (yes/no). The study participants were told that an NMSA was an unplanned driving event that was due to sleepiness and that caused no harm but had the potential to cause harm
The response rate was 80%. Mean age of drivers was 46±13 years and 75.2% of participants were male; 85% of drivers were on vacation and 61% were the only drivers in the vehicle. Total driving distance at the time of the interview was 330±226 Km, with a mean driving duration of 181±108 minutes.
2.9% of drivers reported at least one NMSA during the trip. We found that drivers reporting NMSA during the current trip had a 2.6-fold increase in sleep-related accidents in the past year, compared to drivers without current NMSA.
This finding confirms the strong association between NMSA and driving accidents (7, 8) and suggests that individuals with NMSA may exhibit chronic sleepiness at the wheel. Importantly, non-restorative sleep and snoring were also independently associated with NMSA during the current trip, suggesting a possible association between obstructive sleep apnea syndrome and sleepiness-related car accidents.
Finally, sleepiness during the interview was associated with NMSA during the current trip. Then it seems that unlike previous findings (9), the main risk factors for sleepiness and sleepiness-related NMSA were subjective complaints consistent with non-restorative sleep and snoring.
This finding indicates a change from past studies in which inadequate sleep hygiene was the main source of sleepiness at the wheel and suggests beneficial effects of road-safety campaigns.
In conclusion, risk factors associated with chronic sleepiness at the wheel remains a major challenge for future road safety campaigns. Then more studies of the impact of sleep-related breathing disorders are needed.
1. Nabi H, Gueguen A, Chiron M et al. Awareness of driving while sleepy and road traffic accidents: prospective study GAZEL cohort. BMJ 2006 ; 333 :75
2. Connor J, Norton R, Ameratunga S et al Driver sleepiness and and risk of serious injury to car occupants: population based case control study. BMJ 2002; 324: 1125
3. AFSA. Evolution du facteur Fatigue, Hypovigilance ; Endormissement entre 1997 et 2005. Paris : Association des Sociétés Françaises ; 2007
4. Larue G, Rakotonirainy A, Pettit A. Driving performance impairments due to hypovigilance on monotonous roads. Accid Anal prev 2011; 43: 2037 – 2046
5. ONISR. La sécurité routière en France. Bilan de l’année 2010. Observatoire national interministériel de sécurité routière (ONISR). 2012
6. Quera Salva MA, Barbot F, Hartley S, Sauvagnac R, Vaugier I, Lofaso F, Philip P Sleep Disorders, Sleepiness, and Near-Miss Accidents among Summer Long-Distance Highway Drivers> In press Sleep Medicine.
7. Philip P, Sagaspe P, Lagarde E et al. Sleep Disorders and accidental risk in a large group of regular registered highway drivers. Sleep Med 2010; 11; 973 – 979.
8. Powel N, Schechtman K, Riley R et al. Sleepy driver near-misses may predict accidents risks. Sleep 2007; 30: 331 – 3421.
9. Philip P, Taillard J, Guilleminault C, Quera Salva MA, Bioulac B, Ohayon M. Long distance driving and self-induced sleep deprivation among automobile drivers. Sleep 1999; 22: 475 – 480.

Richard Bogan
Clinical Experience with Sleep Fragmentation in Narcolepsy Requiring Treatment
Narcolepsy is characterized by excessive daytime sleepiness, often hypnagogic hallucinations, sleep paralysis, nocturnal sleep disruption and sometimes cataplexy. This study examines the clinical history of subjects with narcolepsy to determine the frequency of disturbed nocturnal sleep and subsequent pattern of medication usage.
Methods used included a retrospective review of charts of subjects followed at one sleep clinic with a clinical diagnosis of narcolepsy. Data was collected with pre and post treatment assessment using the Epworth Sleepiness Scale (ESS) to assess daytime sleepiness and the SleepMed Insomnia Index (SMI) to measure nocturnal sleep disruption. Other data collected included age, gender, and usage of sedating medications.
Results demonstrate that sleep disruption is seen in subjects with narcolepsy. SMI and ESS scores showed improvement with treatment. Pre and post SMI scores were higher in the group taking sedative hypnotic medications. An insomnia index can be useful to assist the clinician to quantify sleep disruption in narcolepsy and assess the efficacy of therapy. Further evaluation as to correlation of quantifying sleep disturbance and its impact on severity of disease and treatment is suggested.

This Activity is supported by an Unrestricted Educational Grant from Jazz Pharmaceuticals to Stanford University.