1. Ruth Benca, MD PhD Wisconsin Sleep Insomnia and Primary Care

2. Diagnosis requires one or more of the following: difficulty initiating sleep difficulty maintaining sleep waking up too early, or sleep that is chronically nonrestorative or poor in quality Sleep difficulty occurs despite adequate opportunity and circumstances for sleep. Insomnia is not sleep deprivation, but the two may coexist. Insomnia defined American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed.: Diagnostic and coding manual. Westchester, Illinois: American Academy of Sleep Medicine, 2005.

3. At least one daytime impairment related to the nighttime sleep difficulty must be present: Fatigue/malaise Attention, concentration, or memory impairment Social/vocational dysfunction or poor school performance Mood disturbance/irritability Daytime sleepiness Motivation/energy/initiative reduction Proneness for errors/accident at work or while driving Tension headaches, and/or GI symptoms in response to sleep loss Concerns or worries about sleep Insomnia must be associated with daytime impairment American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed.: Diagnostic and coding manual. Westchester, Illinois: American Academy of Sleep Medicine, 2005.

4. Comorbid insomnia Impacts quality of life and worsens clinical outcomes 1,2 Predisposes patients to recurrence 3 May continue despite treatment of the primary condition 4 “Comorbid insomnia”more appropriate than “secondary insomnia,” because limited understanding of mechanistic pathways in chronic insomnia precludes drawing firm conclusions about the nature of these associations or direction of causality. Considering insomnia to be “secondary” may also result in undertreatment. 5 1 Roth T, Ancoli-Israel S. Sleep. 1999;22:S354-S358. 2 Katz DA, McHorney CA. J Fam Pract. 2002;51:229-235. 3 Chang PP, et al. Am J Epidemiol. 1997;146:105-114. 4 Ohayon MM, Roth T. Psychiatr Res. 2003;37:9-15. 5 National Institutes of Health State of the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. National Institutes of Health. Sleep. 2005 Sep 1;28(9):1049-1057.

5. Epidemiology of insomnia General population: 10-15% Clinical Practice: > 50% The prevalence and treatment of primary insomnia have been the most studied (less than 20% of cases) 1,2 Comorbid insomnia accounts for >80% of cases 1 Simon GE,Vonkorff M. Am J Psychiatry. 1997;154:1417-1423. 2 Hajak G. Sleep. 2000; 23:S54-S63.

6. At-risk populations for insomnia Female sex Increasing age Comorbid medical illness (especially respiratory, chronic pain, neurological disorders) Comorbid psychiatric illness (especially depression, depressive symptoms) Lower socioeconomic status Race (African American > White) Widowed, divorced Non-traditional work schedules

7. Why insomnia is a disorder, not just a symptom Relative consistency of insomnia symptoms and consequences across comorbid disorders Course of insomnia does not consistently covary with the comorbid disorder Insomnia responds to different types of treatment than the comorbid disorder Insomnia responds to the same types of treatment across different comorbid disorders Insomnia poses common risk for development of and poor outcome in different disorders Clin Psychol Rev, 2001;Lichstein et al., Treating Sleep Disorders, 2004 Harvey, Clin Psychol Rev, 2001; Lichstein et al., Treating Sleep Disorders, 2004

8. Increased prevalence of medical disorders in those with insomnia Taylor DJ., et al. Sleep. 2007;30(2):213-218. p values are for Odds Ratios adjusted for depression, anxiety, and sleep disorder symptoms. From a community-based population of 772 men and women, aged 20 to 98 years old. Heart Disease Cancer HTN Neuro- logic Breath- ing UrinaryDiabetesChronic Pain GI Any medical problem % N=137 N=401 p<.05 p<.01 p<.001

9. Prevalence, % Survey Of Adults (N=2101) Living In Tucson, Arizona, Assessed Via Self-administered Questionnaires * * ** * * Increased prevalence of insomnia in those with medical disorders Klink ME et al. Arch Intern Med. 1992;152:1634-1637. *P ≤.001, **P ≤.005 vs. no health problem ASVD, arteriosclerotic vascular disease; OAD, obstructive airway disease.

10. Insomnia prevalence increases with greater medical comorbidity Foley D, et al. J Psychosom Res. 2004;56:497-502. Self-reported questionnaire data from 1506 community-dwelling subjects aged 55 to 84 years 80 Number of Medical Conditions 0 10 20 30 40 50 60 70 Percent of Respondents Reporting any Insomnia 0 1 2 or 3 4

11. Psychiatric disorder is the most common condition comorbid with insomnia Adjustment disorder (2%) Anxiety disorder (24%) Bipolar disorder (2%) Depressive disorder (8%) Psychiatric Disorders (36%) Other DSM-IV Distribution of Insomnia(64%) No DSM-IV diagnosis (24%) Other sleep disorders (5%) Insomnia due to a general medical condition (7%) Substance-induced insomnia (2%) Insomnia related to another mental disorder (10%) Primary insomnia (16%) Ohayon MM. Sleep Med Rev. 2002;6:97-111. N=20,536. European meta-analysis

12. Relative risk for psychiatric disorders associated with insomnia 1 Breslau N, et al. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39:411-418. 2 Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA. 1989;262(11):1479-1484. 1 Breslau, 1996. N=1007 2 Ford and Kamerow, 1989. N=811 1 1 1 2 2 1,2

13. Timing of insomnia related to onset of psychiatric illness Ohayon MM, Roth T. J Psychosom Res. 2003;37:9-15. N=14,915

14. * Number of men included at each time point. Chang P et al. Am J Epidemiol. 1997;146:105-114. Insomnia is a risk factor for later-life depression Insomnia* Yes137135133127117106 99 27 9 No887877859838799740616382216 Cumulative Incidence (%) Yes No TotalCases 13723 88776 Insomnia P=.0005 Follow-up Time (Years) 0 5 10 15 20 25 30 35 40 0510152025303540

15. Objective sleep abnormalities are seen in psychiatric patients Comparison of sleep EEG in groups of patients with psychiatric disorders or insomnia to age-matched normal controls. TSTSESLSWSREM L Mood Alcoholism Anxiety Disorders Schizophrenia Insomnia Benca RM et al. Arch Gen Psych. 1992;49:651-668

16. Bidirectional relationship between psychiatric disorders and insomnia ACTH, adrenocorticotropic hormone TST, total sleep time SOL, sleep onset latency SWS, slow wave sleep

17. Sleep and menopause Peri- and postmenopausal women have more sleep complaints 1 41% of early perimenopausal women report sleep difficulties 2 Frequent awakenings suggest insomnia is secondary to vasomotor symptoms 3 However, waking episodes may occur in absence of hot flashes 4 1 Young T, et al. Sleep. 2003;26:667-672. 2 Gold E, et al. Am J Epidemiol. 2000;152:463-473. 3 Woodward S, Freedman RR. Sleep.1994;17:497-501. 4 Polo-Kantola P, et al. Obstet Gynecol. 1999;94:219-224. 1 Young T, et al. Sleep. 2003;26:667-672. 2 Gold E, et al. Am J Epidemiol. 2000;152:463-473. 3 Woodward S, Freedman RR. Sleep.1994;17:497-501. 4 Polo-Kantola P, et al. Obstet Gynecol. 1999;94:219-224.

18. Age Group, y 50 40 30 20 10 0 Percent 10-19 20-29 30-39 40-49 50-59 60-69 70+ “Trouble With Sleeping” Assessed in a comprehensive survey of 1645 individuals in Alachua County, Florida Complaints of sleep problems with age Karacan I et al. Soc Sci Med. 1976;10:239-244.

19. Prevalence of insomnia by age group % Age Group, years Large-scale community survey of non-institutionalized American adults, aged 18 to 79 years Mellenger GD, et al. Arch Gen Psychiatry. 1985;42:225-232.

20. Patients with pain report poor sleep 287 subjects reporting to pain clinic Mean age, 46.7 years; half with back pain 89% reported at least 1 problem with sleep Significant correlations between sleep and Physical disability Psychosocial disability Depression Pain McCracken LM, Iverson GL. Pain Res Manag. 2002;7:75-79.

21. Insomnia comorbid with pain N=18,980; p<.001. Based on survey data. *Pain categories included limb pain, backaches, joint pain, GI pain, and headaches. Ohayon MM. J Psychiatr Res. 2005 Mar;39(2):151-159. Control Any pain* %

22. Bidirectional relationship between pain and insomnia DIS, difficulty initiating sleep DMS, difficulty maintaining sleep

23. Sleep and cancer 30% to 75% of newly diagnosed or recently treated cancer patients complain of insomnia (double that of the general population) Sleep complaints in cancer patients consist of difficulty falling asleep difficulty staying asleep frequent and prolonged nighttime awakenings Complaints occur before, during and after treatment Fiorentino L, Ancoli-Israel, S. Sleep dysfunction in patients with cancer. Curr Treat Opt Neurol. 2007;9:337–346.

24. Risk factors for insomnia in cancer patients Risk FactorExamples Disease factors Tumors that increase steroid production, symptoms of tumor invasion (pain, dyspnea, fatigue, nausea, pruritis) Treatment factors Frequent monitoring, corticosteroid treatment, hormonal fluctuations, fatigue Medications Narcotics, chemotherapy, neuroleptics, sympathomimetics, sedative/hypnotics, steroids, caffeine/nicotine, antidepressants, diet supplements Environmental factorsDisturbing light and noise, temperature extremes Psychosocial disturbancesDepression, anxiety, delirium, stress Physical disordersHeadaches, seizures, snoring/sleep apnea O'Donnell JF. Clin Cornerstone. 2004;6(Suppl 1D):S6-S14.

25. Bidirectional relationship between insomnia and cancer SDB, sleep-disordered breathing Fiorentino L, Ancoli-Israel, S. Sleep dysfunction in patients with cancer. Curr Treat Opt Neurol. 2007;9:337–346.

26. Insomnia and OSA or CSA Studies have shown that 39% to 55% of patients with OSA have comorbid insomnia. Associated factors include: female gender psychiatric diagnoses chronic pain OSA patients with comorbid insomnia have More severe sleep apnea Increased depression, anxiety and stress Krell SB, Kapur VK. Sleep Breathing. 2005;9:104-10. Smith S, et al. Sleep Med. 2004;5:449-456. AHI, apnea hypopnea index. CSA, central sleep apnea. DI, desaturation index. OSA, obstructive sleep apnea. restless leg symptoms lower AHI, lower DI

27. Insomnia and OSA or CSA < 1% of 1,000 patients with OSA surveyed had been diagnosed with insomnia Mood problems were not formally addressed In a small study of patients with CSA (n=14): 36% had sleep onset insomnia 79% had maintenance insomnia This rate was significantly higher than in patients with OSA (P =.016) Morganthaler TI,et al. Sleep. 2006;29:1203-1209. Smith S, et al. Sleep Med. 2004;5:449-456.

28. Insomnia and COPD >50% of patients with COPD have insomnia 25% complain of excessive daytime sleepiness Medications for COPD contribute to insomnia Inhaled or PO; anticholinergics, corticosteroids, beta-2-agonists, theophylline; bupropion used for smoking cessation Sleep deprivation may attenuate ventilatory response to hypercapnia in patients with COPD, leading to further desaturation and sleep disruption George CFP. Sleep. 2000;23:S31-S35. White DP, et al. Am Rev Respir Dis. 1983;128:984-986.

29. Insomnia and COPD Insomnia linked with comorbidities of COPD Eg, depression, smoking, orthopnea, and nocturnal hypoxemia Suggests multiple factors in pathogenesis of insomnia in COPD Insomnia can impair pulmonary function Spirometric decline is observed after one night of sleep deprivation Despite importance of treating the underlying COPD, this may not lead to improvement of insomnia in clinical practice Cormick W, et al. Thorax. 1986;41:846-854. Kutty K. Curr Opin Pulm Med. 2004;10:104-112. Maggia S, et al. J Am Geriatric Soc. 1998;46:161-168. Phillips BA, et al. Chest. 1987;91:29-32. Wetter DW, et al. Prev Med. 1994;23:328-334.

30. Insomnia may be a predictor of hypertension N=9237 male Japanese workers assessed for difficulty initiating and/or maintaining sleep and followed up for 4 years or until the development of HTN (initiation of anti-HTN therapy or a SBP of ≥140 mmHg or a DBP of ≥140 mmHg). Results adjusted for BMI, tobacco and alcohol use and job stress. Suka M, et al. J Occup Health. 2003;45:344-350. HTN Incidence (%) n=4602 n=192 n=4157 n=286 95% CI: 1.42-2.70 95% CI: 1.45-2.45

31. Short sleep duration and hypertension: NHANES I and the Sleep Heart Health Study Gangwisch et al. Hypertension. 2006;47:833-839. Gottlieb DJ, et al. Sleep. 2006;29(8):1009-1014. ≤5h 6h 7-8h ≥9h ≤6h 6-7h 7-8h 8-9h ≥9h (1.0; referent) Hazard Ratios. N=4180. Subjects 32-59y. Sleep duration and increased risk of HTN, adjusted for multiple confounders including physical activity, alcohol/salt consumption, smoking, age, overweight/obesity, and diabetes. Odds Ratios. N=5910. Subjects 40- 100y. Sleep duration and increased risk of HTN adjusted for age, sex, race, apnea- hypopnea index and BMI.

32. Relationships between sleep disorders* and obesity * Insomnia or sleep deprivation. 1 Bjorvatn B, et al. J Sleep Res. 2007;16(1):66-76. 2 Flint J, et al. J Pediatr. 2007;150(4):364-369. 3 Chaput JP, et al. Obesity (Silver Spring). 2007;15(1):253-261. 4 Gottlieb et al. Arch Intern Med. 2005;165:863-868. Factors associated with reduced sleep time* may contribute to obesity

33. Management of insomnia Treat any underlying cause(s)/comorbid conditions Promote good sleep habits (improve sleep hygiene) Consider cognitive behavior therapy Consider medications to improve sleep Kupfer DJ and Reynolds CF III. N Engl J Med. 1997;336:341-346.

34. Practicing good sleep hygiene Avoid: “watching the clock” use of stimulants, eg, caffeine, nicotine, particularly near bedtime 1,3 heavy meals or drinking alcohol within 3 hours of bed 1 exposure to bright light during the night 1,3 Enhance sleep environment: dark, quiet, cool temperature 1,3 Increase exposure to bright light during the day 2 Practice relaxing routine 1-3 Reduce time in bed; regular sleep/wake cycle 1-3 Time regular exercise for the morning and/or afternoon 1,3 1 NHLBI Working Group on Insomnia. 1998. NIH Publication. 98-4088. 2 Kupfer DJ, Reynolds CF. N Engl J Med. 1997;336:341-346. 3 Lippmann S et al. South Med J. 2001;94:866-873.

35. Behavioral techniques TechniqueAim Stimulus control therapy Imprint bed and bedroom as sleep stimulus Sleep restriction Restrict actual time spent in bed to enhance sleep depth & consolidation Cognitive therapyAddress dysfunctional beliefs and attitudes about sleep Relaxation trainingDecrease arousal and anxiety Circadian rhythm entrainment Reinforce or reset biological rhythm using light and/or chronotherapy Cognitive behavior therapy Combination of behavioral and cognitive approaches listed above

36. Drugs indicated for insomnia * Modified formulation. † No short-term use limitation. GenericBrandT 1/2 (Hours)Dose (mg)Drug Class FlurazepamDalmane48-12015-30BZD TemazepamRestoril8-2015-30BZD TriazolamHalcion2-60.125-0.25BZD EstazolamProsom8-241-2BZD QuazepamDoral48-1207.5-15BZD ZolpidemAmbien1.5-2.45-10non-BZD ZaleplonSonata15-20non-BZD Eszopiclone † Lunesta5-71-3non-BZD Zolpidem Ex Rel † Ambien CR1.5-2.4*6.25-12.5non-BZD Ramelteon † Rozerem1.5-58MT agonist

37. Antidepressants for Insomnia: Indications Patients with psychoactive substance use disorder history Patients with insomnia related to depression, anxiety Treatment failures with BzRA Suspected sleep apnea Fibromyalgia Primary insomnia (second-line agents) Not FDA-approved for use as hypnotics

38. Antidepressant drug effects on sleep Sleep continuity Slow wave sleep REM sleepOther Tricyclic  To  To   To     PLMs  Apnea SSRI  To   To   Eye movements in NREM  PLM  apnea Trazodone, Nefazodone   To  Trazodone more sedating Bupropion   To   No increase in PLM Mirtazapine  Low doses sedating

40. When to refer an insomnia patient to Sleep Clinic: Medical and psychiatric comorbidities have been assessed and are adequately treated Patient has been instructed in sleep hygiene Patient has failed trials of behavioral and/or pharmacological therapy

41. Other common sleep disorders treated by sleep specialists: Sleep apnea* Restless legs/periodic limb movement disorder Parasomnias Circadian rhythm disorders Narcolepsy* *Typically require sleep laboratory testing as well as clinical evaluation for diagnosis

45. High density-EEG / TMS studies in health and disease pioneered by Giulio Tononi, MD, PhD High density EEG (256 electrodes) recorded across entire night, TMS in wakefulness and sleep

46. Why high-density EEG in sleep? Can now be done routinely; noninvasive and relatively inexpensive What could be done with standard PSG has largely been done (NIH roadmap discourages it) Sleep apnea PSG likely to migrate to home-monitoring Spatial resolution is comparable to PET; temporal resolution is ideal Sleep is a window on spontaneous brain function, unconfounded by attention, motivation, etc. Broad patient population: sleep disorders, psychiatric disorders, neurological disorders (and connection to long-term epilepsy monitoring)

47. Spontaneous brain rhythms during sleep reflect brain functioning unconfounded by attention and motivation slow wave activityspindle activity

48. Fz Cz P4 Sleep Slow Wave Activity is Homeostatically Regulated Throughout the Cortex

49. Slow waves originate more frequently in orbitofrontal and centroparietal regions and propagate in an antero-posterior direction

50. P<.05 100 80 60 40 20 Schizophrenics Controls Depressed Schizophrenics vs. Controls Schizophrenics vs. Depressed Depressed vs. Controls EEG spindle activity (13-15 Hz) Diagnosis: Sleep spindle activity is reduced in schizophrenia Ferrarelli et al., Am. J. Psychiatry, 2007

51. Treatment: Sleep slow oscillations can be triggered by TMS Massimini et al., submitted

52. Sleep Clinic and 16 Bed Sleep Laboratory - UWMF clinic - Sleep Laboratory joint venture with Meriter Open with 12 beds, 5 nights/week Clinic operates 5 days/week Staff model - approx 30 FTE Sleep Equipment of Wisconsin - UWHC/Meriter joint venture

53. Psychiatry R. Benca, MD, PhD M. Rumble, PhD Pulmonary M. Klink, MD S. Cattapan, MD J. McMahon, MD G. DoPico, MD Mihaela Teodorescu, MD Geriatrics S. Barczi, MD Mihai Teodorescu, MD Pediatrics C. Green, MD Neurology J. Jones, MD Interdisciplinary Clinical Expertise

54. Clinical Practice Model: Clinic Referral-based practice. Improve access. Standardized assessments of all patients using validated questionnaires, comprehensive evaluations, outcomes measures. All information on electronic database. Development of behavioral sleep medicine program. Outreach to primary care.

55. Clinical Practice Model: Laboratory Encourage referring providers to request studies with management. Laboratory studies read the next morning. Timely communication with referring physicians; reports sent and/or available electronically within 24 hours of completion. Sleep Equipment of Wisconsin on-site to provide immediate availability of treatment.

56. Educational program Directed by Steven Barczi, MD ACGME-accredited fellowship Currently only 1 position; application for up to 3 slots per year pending Plan to coordinate medical school and residency training in sleep Lectures in medical school and residency curricula Clinical electives

57. Translational research opportunity Brand new program Standardized assessment and outcomes measures State-of-the-art neurophysiological recording techniques Every patient a potential research subject