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Insomnia: Special Considerations for Specific Populations of Women

Insomnia: Special Considerations for Specific Populations of Women. Kin M. Yuen, MD, MS FAASM, D, ABSM Medical Director Bay Sleep Clinic, CA. Sleep Needs Vary by Age. Infants: 16-18 hours of total sleep time (TST) daily Begin nocturnal sleep with rapid eye movement (REM) cycle Age 1:

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Insomnia: Special Considerations for Specific Populations of Women

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  1. Insomnia: Special Considerations for Specific Populations of Women Kin M. Yuen, MD, MS FAASM, D, ABSM Medical Director Bay Sleep Clinic, CA

  2. Sleep Needs Vary by Age • Infants: • 16-18 hours of total sleep time (TST) daily • Begin nocturnal sleep with rapid eye movement (REM) cycle • Age 1: • ↓ to 14 hours of total daily sleep • Begins “adult pattern” of alternating nonREM to REM cycles

  3. Average Hours of Sleep Vary by Age Iglowstein I, Jenni OG, Molinari L, Largo RH. Pediatrics. 2003;111:302-307.

  4. Adolescence • Slow-wave sleep (SWS) begins to decline • Tendency toward later time to bed and time to rise: • Delayed sleep phase syndrome

  5. Normal Sleep for Healthy Adults • Average total nocturnal sleep time is 7.5-8 hours • Sleep latency: 10-15 minutes • Sleep stages of TST • 5% stage 1 • 50% stage 2 • 15%-25% stages 3 and 4 SWS • 20%-25% REM Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV.Sleep. 2004;27:1255-1273.

  6. Aging • More lighter stages of sleep (stage 1) • Less SWS • Women with more preserved SWS objectively • Age 60->70 years • Men 6-7% TST • Women 17% TST • Women with more subjective complaints Redline S, Kirchner HL, Quan SF, Gottlieb DJ, Kapur V, Newman A.Arch Intern Med. 2004;164:406-418.

  7. Insomnia is Highly Prevalent • Chronic insomnia is estimated to affect 10% (range 9%-24%) of the population1 • 30% to 50% of the general population are estimated to have insomnia of any duration or severity • “The prevalence of insomnia symptoms generally increases with age, while the rates of sleep dissatisfaction and diagnoses have little variation with age”2 1. Agency for Healthcare Research and Quality. Manifestations and Management of Chronic Insomnia in Adults. http://www.ahrq.gov/downloads/pub/evidence/pdf/insomnia/insomnia.pdf. Accessed February 11, 2008. 2. Ohayon MM. Sleep Med Rev. 2002;6:97-111.

  8. National Sleep Foundation 2003 Poll • One or more symptoms of a sleep problem • Age 55-64: 71% • Age 65-74: 65% • Age 75-84: 64% • Insomnia with more than 1 symptom • Women: 50% • Men: 45% • 22% age 55-64 and 46% age 75-84 nap 1-3 times/week National Sleep Foundation. 2003 Sleep in America Poll. http://www.kintera.org/atf/cf/{F6BF2668-A1B4-4FE8-8D1A-A5D39340D9CB}/2003SleepPollExecSumm.pdf. Accessed February 11, 2008/

  9. Menstrual Cycle • Early in the cycle: more airway resistance • Pain/discomfort disturbed sleep • Later cycle • Excessive daytime sleepiness • Insomnia: trouble falling asleep, staying asleep, nonrefreshing sleep

  10. Hormonal Effects on Sleep • Inconsistentreported effects on SWS • Estrogen  Turnover of norepinephrine in brain  Variable effects on REM sleep

  11. Hormonal Effects • Estrogen • Variable effect on REM1 • Progesterone • Sedating2 • Increases NREM2 • Lack/withdrawal: difficulty falling asleep2 1. Manber R, Kuo TF, Cataldo N, Colrain IM. Sleep. 2003;26:163-168. 2. Eichling PS, Sahni J. J Clin Sleep Med. 2005;1:291-300.

  12. Estrogen and Sleep • Humans:  REM sleep cycles1 •  REM sleep latency?1 •  Number of spontaneous arousals1 • Postestrogen replacement •  Sleep onset latency (SOL)2 •  Wake after sleep onset (WASO) •  TST •  REM2 and SWS3 1. Eichling PS, Sahni J. J Clin Sleep Med. 2005;1:291-300. 2. Schiff I, Regestein Q, Tulchinsky D, Ryan KJ. JAMA. 1979;242:2405-2404. 3. Manber R, Kuo TF, Cataldo N, Colrain IM. Sleep. 2003;26:163-168.

  13. Hormonal Effects on Sleep • Progesterone •  NREM sleep1 • Exogenous: • Benzodiazepine-like sedation in men and women1 • Active metabolites: Pregnanolone1 • α-aminobutyric acid (GABA) receptor1 • Dose-dependent  sleep onset (SO),  WASO • May  sleep spindle frequency Manber R, Armitage R. Sleep. 1999;22:540-555.

  14. Sleep and the Menstrual Cycle • SO and maintenance insomnia • Overall:  subjective sleep complaints late luteal phase •  SOL •  Wake after SO • ↓ Sleep efficiency

  15. Menstrual-related Sleep Disorder • Changes in sleep architecture: •  SWS •  REM •  SO latency •  Wakefulness after SO •  Sleep efficiency

  16. Sleep and Pregnancy • Subjective complaints • Excessive daytime sleepiness1 • Many hormones responsible • Progesterone, β-human chorionic gonadotropin, prolactin, luteinizing hormone •  Fatigue,  body temperature • Shortness of breath Franklin KA, Holmgren PA, Jönsson F, Poromaa N, Stenlund H, Svanborg E. Chest. 2000;117:137-141.

  17. Sleep and Pregnancy (cont’d) • Severe insomnia • Abdominal mass, fetal movements, bladder distention • Others: leg cramps, acid reflux, backache • Primiparous >multiparous in sleep disturbances

  18. First trimester:  TST,  SWS Second trimester: TST nla  SWS/REM Third trimester:  TST,  SO  WASO Arousals/awakenings(3-5x)  REM  SWS  Sleep efficiency Sleep in Pregnancy a19% persistent problem Lee KA, Zaffke ME, Baratte-Beebe K. J Womens Health Gend Based Med. 2001;10:335-341.

  19. Pregnancy and Snoring • 23% women report onset of snoring in pregnancy(third trimester)1 • 14% reported snoring often or always (4% of nonpregnant)1 • Snoring during pregnancy is associated with hypertension and preeclampsia2 • Obstructive sleep apnea syndrome: case reports, intrauterine growth retardation (IUGR)1 • Especially obese women3, polycystic ovary syndrome 1. Loube DI, Poceta JS, Morales MC, Peacock, MD, Mitler MM. Chest. 1996;109:885-889. 2. Edwards N, Middleton PG, Blyton DM, Sullivan CE. Thorax. 2002;57:555-558. 3. Franklin KA, Holmgren PA, Jönsson F, Poromaa N, Stenlund H, Svanborg E. Chest. 2000;117:137-141

  20. Pregnancy: Periodic Limb Movement, Restless Leg Syndrome • May be associated with: • Fe deficiency anemia • Type-2 diabetes • Uremia • Symptoms usually subside postpartum • 15%-25%1,2 women develop restless leg syndrome in third trimester • Conservative treatment before third trimester–avoid caffeine 1. Lee KA, Zaffke ME, Baratte-Beebe K. J Womens Health Gend Based Med. 2001;10:335-341. 2. Goodman JDS, Brodie C, Ayida GA: Restless legs syndrome in pregnancy. BMJ 1998;297:1101-1102.

  21. Postpartum Sleep • 30% new mothers report disturbed sleep • Sleep efficiency in first 2-4 weeks <third trimester • Average 2 hours time of wakefulness (WASO) • First-time mothers’ sleep most disturbed • Some rebound of stage 4, but  REM • Women with premature infants have  TST,  WASO • Alterations in melatonin, cortisol Wolfson AR, Lee KA. Pregnancy And The postpartum period: sleep during postpartum recovery. In: Kryger MH, Roth T, Dement W. Principles and Practice of Sleep Medicine.4th ed. Philadelphia, PA:Saunders; 2005:1280-1281.

  22. Postpartum Depression and Sleep • Nighttime labor (↑oxytocin) and sleep disruptions (third trimester) associated with depressed mood after childbirth •  REM latencies associated with depressed mood • Likely multifactorial; heightened reaction to stress

  23. Postpartum Depression • Baby blues • Very common: 50%-80% of all new mothers • 2 weeks after delivery: about Day 3 to Day 5 • Postpartum depression • 10%-20% of new mothers • May last up to 1 year • Major depression symptoms • 50% with past history of depression • Insomnia to overwhelming fatigue • Negative feelings toward baby, resentment • Postpartum psychosis • Rare: 0.1% of new mothers • 3 weeks after delivery • Past history of bipolar disorder Cohen LS, Altshuler LL, Harlow BL, et al. JAMA. 2006;295:499-507.

  24. Persistent Major Depression • Of 201 women who discontinued antidepressants, 86 (43%) relapsed throughout pregnancy • 82 controls maintained medication, 21 (26%) relapsed • Hazard ratio 5.0, 2.8-9.1; P<0.001 Cohen LS, Altshuler LL, Harlow BL, et al. JAMA. 2006;295:499-507.

  25. Pregnancy Summary 1 • First trimester • ↑ TST • Second trimester • ↓ SWS and REM sleep • Third trimester • Fragmented sleep

  26. Pregnancy Summary 2 • General decrease in parasomnia • Beware of new onset snoring before second trimester; correlation with preeclampsia • Restless legs movement more common in third trimester • Postpartum depression in 10%-20% of new mothers • Antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs] may be justified) Cohen LS, Altshuler LL, Harlow BL, et al. JAMA. 2006;295:499-507.

  27. Narcolepsy1,2 • Disability/early maternity leave • Letter to employer to allow naps • Avoid medications during first trimester and when nursing • If benefit outweighs risks: • Cataplexy: GHB/SSRIs • Insomnia: GHB or zolpidem • Excessive daytimes sleepiness: weaker stimulants/modafinil • Pregnancy test before initiating medications? 1. Morgenthaler TI, Kapur VK, Brown T, et al. Sleep. 2007;30:1705-1711. 2. Wise MS, Arand DL, Auger RR, Brooks SN, Watson NF; American Academy of Sleep Medicine. Sleep. 2007;30:1712 1727.

  28. Stimulants 1. The Physician’s Desk reference Web site. http: www.pdr.net. Accessed March 10, 2008. 2. Wake-Promoting Medications: Efficacy and Adverse Effects. In: Kryger MH, Roth T, Dement W. Principles and Practice of Sleep Medicine.4th ed. Philadelphia, PA: Saunders; 2005:1280-1281.

  29. Insomnia and Menopause Cláudio N. Soares, MD, PhD, FRCPCAssociate Professor of Psychiatry and Behavioral Neurosciences Director, Women’s Health Concerns ClinicMcMaster University, Ontario, CanadaLecturer in Psychiatry Harvard Medical SchoolBoston, Massachusetts

  30. Disclosures • Grants/research support: National Alliance for Research on Schizophrenia and Depression (NARSAD); Eli Lilly and Company; AstraZeneca Pharmaceuticals LP (Canada); Physicians Service Incorporated (PSI) (Canada); Allergen, Inc. (Canada) • Consultant: Forest Laboratories, Inc.; GlaxoSmithKline (Canada); Neurocrine Biosciences, Inc.; Sepracor Inc.; Concert Pharmaceuticals; Wyeth Pharmaceuticals Inc. • Speaker’s bureau: AstraZeneca Pharmaceuticals LP (Canada); Forest Laboratories, Inc.; GlaxoSmithKline (Canada); H. Lundbeck A/S (Canada); Pfizer Inc.; Wyeth Pharmaceuticals Inc. (Canada)

  31. Insomnia Is More Prevalent In Women1,2 • Various studies have identified female gender as a strong risk factor for insomnia • Overall, women are about 1.4 times more likely to report insomnia than men • Heightened psychiatric morbidity and different impact of sex steroids may play an important role 1. Ohayon MM. Sleep Med Rev. 2002;6:97-111.2. Soares CN, Murray BJ. Psychiatr Clin North Am. 2006;29:1095-1113.

  32. Risk Factors for Insomnia1-3 1. Buscemi N, Vandermeer B, Friesen C, et al. (Prepared by the University of Alberta Evidence-based Practice Center, under Contract No. C400000021.) AHRQ Publication No. 05-E021-2. Rockville, Md: Agency for Healthcare Research and Quality. June 2005. Available at: http://www.ahrq.gov/downloads/pub/evidence/pdf/insomnia/insomnia.pdf. Accessed January 29, 2008.2. Doghramji PP. J Clin Psychiatry. 2004;65(suppl 16):23-26.3. Doghramji PP. J Clin Psychiatry. 2001;62(suppl 10):18-26.

  33. Insomnia and Comorbid Conditions:An Important Factor During Menopause? • Insomnia is highly prevalent among patients with other medical and psychiatric illnesses and may: • Worsen clinical outcomes and impact quality-of-life (QoL)1 • Predispose patients to recurrence2 • Persist despite treatment of the primary condition3 • What happens during the menopausal transition? 1. Katz DA, McHorney CA. J Fam Pract. 2002;51:229-235.2. Chang PP, Ford DE, Mead LA, Cooper-Patrick L, Klag MJ. Am J Epidemiol. 1997;146:105-114.3. Ohayon MM, Roth T. Psychiatr Res. 2003;37:9-15.

  34. What about women during the menopausal transition and postmenopausal years?

  35. Menopausal Women Report a Variety of Symptoms: Physiological, Psychological, and Somatic Physiological Symptoms • Hot flashes (day and night)1 • Sleep disturbances1,2 • Urogenital complaints3 Psychological Symptoms • Irritability1,2 • Depressive symptoms4,5 • Mood disturbances1 • Low libido6 Somatic Symptoms • Aches and pain7 • Fatigue1 1. Kronenberg F. Ann N Y Acad Sci. 1990:592:52-68. 2. Bachmann GA. J Reprod Med. 2005;50:155-165. 3. Cedars MI, Evans M. Menopause. In: Scott JR, Gibbs RS, Karlan BY, Haney AF, eds. Danforth‘s Obstetrics and Gynecology. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:721-737. 4. Bromberger JT, Meyer PM, Kravitz HM, et al. Am J Public Health. 2001;91:1435-1442. 5. Schmidt PJ, Haq N, Rubinow DR.Am J Psychiatr. 2004;161:2238-2244. 6. Dennerstein L, Dudley E, Burger H. Fertil Steril. 2001;76:456-460. 7. Dugan SA, Powell LH, Kravitz HM, et al. Clin J Pain. 2006;22:325-331.

  36. Menopause FMP Hormonal fluctuations Premenopausal years Postmenopausal years Adapted from: Cedars MI, Evans M. Menopause. In: Scott JR, Gibbs RS, Karlan BY, Haney AF, eds. Danforth‘s Obstetrics and Gynecology. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:721-737.

  37. Window of Vulnerability1-3 • Heightened prevalence of mood and sleep disturbances during periods of intense hormone variability/fluctuation • Adverse outcomes resulting from the disruption of hormone milieu 1. Soares CN. Expert Rev Neurother. 2007;7:1285-1293. 2. Rocca W, Bower JH, Maraganore DM, et al. Neurology. 2007;69:1074-1083.3. Almeida OP, et al. Arch Gen Psychiatry. 2007; In press.

  38. Window of Opportunity1,2 • A stable hormone milieu or hormone interventions may exert a prophylactic (eg, neuroprotective) effect • Hormone intervention/modulation may exert a therapeutic effect 1. Soares CN, Almeida OP, Joffe H, Cohen LS. Arch Gen Psychiatry. 2001;58:529-534. 2. Rocca WA, Bower JH, Maraganore DM, et al. Neurology. 2007;69:1074-1083.

  39. Sleep and Menopause • Peri- and postmenopausal women have more sleep complaints than younger women1 • 41% of early perimenopausal women report sleep difficulties2; many are at higher risk for developing depressive symptoms • Frequent awakenings • Difficulty falling back to sleep • Difficulty falling asleep 1. Young T, Rabago D, Zgierska A, Austin D, Laurel F. Sleep. 2003;26:667-672.2. Gold EB, Sternfeld B, Kelsey JL, et al. Am J Epidemiol. 2000;152:463-473.

  40. Sleep and Menopause (cont’d) • Frequent awakenings suggest insomnia is secondary to vasomotor symptoms1 • More common in women with surgical menopause • However, waking episodes may occur in absence of hot flashes2,3 1. Woodward S, Freedman RR. Sleep. 1994;17:497-501.2. Polo-Kantola P, Erkkola R, Irjala K, et al. Obst Gynecol. 1999;94:219-224.3. Harlow B, et al. Arch Gen Psychiatry. In press.

  41. Sleep-disordered Breathing in Menopause • The prevalence of obstructive sleep apnea syndrome (OSAS) in women appears to increase with age. Diminishing progesterone levels during menopause may be a cause of OSAS, as progesterone is a known respiratory stimulant and upper airway dilator1 • Increased body weight associated with menopause may also be a cause. However, menopause is associated significantly with increased risk of OSAS, independently of body weight2 • Some of this effect may be mediated by testosterone, which may decrease the threshold for the occurrence of apnea3 1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. N Engl J Med. 1993;328;1230-1235. 2. Young T, Rabago D, Zgierska A, Austin D, Laurel F. Sleep. 2003;26:667-672. 3. Zhou XS, Rowley JA, Demirovic F, Diamond MP, Badr MS. J Appl Physiol. 2003;94:101-107.

  42. Treatment of Insomnia in Symptomatic Women During Menopausal Transition or Postmenopause1-5 • Overall, sleep hygiene measures, sleep agents, and behavioral approaches might be helpful • Few studies have focused on these specific subpopulations. Among these, positive results have been described with use of: - Hormonal therapy - Antidepressants (with comorbid conditions) - Hypnotic agents 1. Dorsey CM, Lee KA, Scharf MB. Clin Ther. 2004;26:1578-1586. 2. Polo-Kantola P, Erkkola R, Irjala K, Pullinen S, Virtanen I, Polo O. Fertil Steril. 1999;71:873-880. 3. Gambacciani M, Ciaponi M, Cappagli B, et al. Maturitas. 2005;50:91-97. 4. Joffe H, Soares CN, Petrillo LF, et al. J Clin Psychiatry. 2007;68:943-950. 5. Soares CN, Joffe H, Rubens R, Caron J, Roth T, Cohen L. Obstet Gynecol. 2006;108:1402-1410.

  43. Sleep Hygiene Rules1,2 1. Stepanski EJ, Wyatt JK. Sleep Medicine Reviews. 2003;7:215-225.2. Hauri P. The sleep disorders. 2nd ed. Kalamazoo, Michigan: Upjohn Pharmaceuticals, 1977.

  44. Sleep Hygiene Rules1,2(cont’d) 1. Stepanski EJ, Wyatt JK. Sleep Medicine Reviews. 2003;7:215-225.2. Hauri P. The sleep disorders. 2nd ed. Kalamazoo, Michigan: Upjohn Pharmaceuticals, 1977.

  45. Estrogen in the Management of Sleep Disturbance • Estrogen improves sleep quality in menopause • Improvement in sleep only partially associated with reduction in hot flashes • Estrogen is likely impacting sleep independent of vasomotor symptoms

  46. Sleep Improvements With Hormone Therapy Sleep Improved More Tired More Restless Less Awakenings Harder Falling Asleep More Morning Tiredness Sleep Generally Improved • Sleep disturbance improved in symptomatic and asymptomatic women Fully Disagree No Difference Fully Agree Polo-Kantola P, Erkkola R, Helenius H, Irjala K, Polo O. Am J Obstet Gynecol. 1998;178:1002-1009.

  47. Vasomotor Score Control Group CE 0.3+MPA CE 0.3+P 10 8 6 4 2 0 a a a 0 4 8 12 Weeks 10 8 6 4 2 0 Sleep Score a a a b b b 0 4 8 12 Weeks Low-dose Hormone Therapy With Micronized Progesterone or Medroxyprogesterone Acetateand Sleep • Low-dose Estrogen (Premarin 0.3 mg) improved sleep scores over placebo • Micronized progesterone (MP) had a greater benefit than medroxyprogesterone acetate (MPA) 2.5 mg aP<0.05 vs corresponding baseline and control group levels bP<0.05 corresponding control and CE + MPA group values Gambacciani M, Ciaponi M, Cappagli B, et al. Maturitas. 2005;50:91-97.

  48. Effects of Hormone Therapy on Sleep Polysomnography in Postmenopausal Women CEE, conjugated equine estrogens; PROG, progesterone; HF, hot flashes; WASO, wake time after sleep onset 1. Pickett CK, Regensteiner JG, Woodard WD, et al. J Appl Physiol. 1989;66:1656-1661.2. Purdie DW, Empson JA, Crichton C, Macdonald L. Br J Obstet Gynaecol. 1995;102:735-739.3. Scharf MB, McDannold MD, Stover R, Zaretsky N, Berkowitz DV. Clin Ther. 1997;19:304-311.4. Polo-Kantola P, Erkkola R, Irjala K, et al.Fertil Steril. 1999;71:873-880.5. Montplaisir J, Lorrain J, Denesle R, Petit D. Menopause.2001;8:10-16.

  49. 25 Escitalopram Hormone Therapy 20 15 Median Scores 10 5 0 MADRS MADRS MENQOL MENQOL Baseline Week 8 Baseline Week 8 Treatment With Escitalopram vs MHT for Menopause-related Depression and Quality-of-Life • Changes from baseline in depressive scores (MADRS), and in QoL (MENQOL) and after 8 weeks of treatment with escitalopram (n=16) or hormone therapy (n=16); LOCF analyses Soares CN, Arsenio H, Joffe H, et al. Menopause. 2006;13:780-786.

  50. Escitalopram vs Hormone Therapy on Sleep Among Depressed and Menopausal Women • Hormone therapy: improvement in PSQI total scores, sleep quality, disturbance (P<0.05). Escitalopram: improvement in PSQI total scores, sleep quality, daytime dysfunction (P<0.05) Soares CN, Arsenio H, Joffe H, et al. Menopause. 2006;13:780-786.

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