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Sleep, sleep disturbances and Sleep disorders Professor Tung-Ping Su, MD Department of Psychiatry National Yang-Ming University Taipei Veterans General.

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Presentation on theme: "Sleep, sleep disturbances and Sleep disorders Professor Tung-Ping Su, MD Department of Psychiatry National Yang-Ming University Taipei Veterans General."— Presentation transcript:

1 Sleep, sleep disturbances and Sleep disorders Professor Tung-Ping Su, MD Department of Psychiatry National Yang-Ming University Taipei Veterans General Hospital Lecture for the IBS, National Yang-Ming University Dec. 09, 2014, Lecture for the IBS, National Yang-Ming University

2 What is sleep? Defined as a reversible state of perceptual disengagement from and unresponsiveness to environment. A complex state compared with wakefulness: changes in physiologic and behavioral process Sleep is physiologic, necessary, temporary, reversible and cyclic

3 Distribution of sleep stage Updated stage: W (wakeful), N1, N2, N3 (NREM) or R(REM) Classic stage: 1, 2, 3 & 4 or R deep or paradoxical slow wave sleep sleep

4 Sleep stages across lifespan child

5 Factors affecting sleep in older people

6 Consequences of abnormal sleep Effects of 3 nights of no sleep and chronic Sleep restriction obtained with Psychomotor Vigilance task (PVT) Lapses: missed or ignored visual cues to perform The task




10 WASO (wakefulness after sleep onset) increased with aging

11 Sleep disturbances

12 正視失眠問題 從流行病學角度來看,保守估計全台灣大 約有 150~200 萬的人飽受失眠之苦 由於慢性失眠可能導致的社會問題 意外或交通事故 ( 高四倍 ) 個人健康、家庭生活與人際關係的干擾 因為注意力及記憶力障礙造成的損失 ( 慢性失眠者比睡眠良好的人認知功能 表現降低大約 20% )

13 Insomnia diagnosis 6% Insomnia symptoms with Daytime consequences 10%-12% Insomnia symptoms Overall prevalence 35% Adapted from Buysse DJ et al. Primary Psychiatry. 2005;12:37-44. Overall prevalence Symptomatic with consequences Actually diagnosed How Common Is Insomnia? (prevalence) Sleep dissatisfaction: 15%

14 Taiwan society of sleep medicine, 2006 A Telephone Survey in 2006 20.2% 14.6% 13.5% 13.3% 24.8% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% Difficulty in Initiation Nonrestorative Sleep Interrupted Sleep Early Morning Awakening TOTAL Unit: % 【 n=4,011 】

15 A Telephone Survey in 2009 TSSM, 2009

16 A Telephone Survey in 2006 11.5% 9.9% 13.2% 【 n=4,011 】 P < 0.01 Taiwan society of sleep medicine, 2006

17 40-4445-5455-6465-74>=75 6.60%6.20%6.90%10.30% 6.60%9.20%9.90%12.60% 40-4445-5455-6465-74>=75 5.50%5.30%7%8.65%8.40% 5.20%6.70%12%16% 40-4445-5455-6465-74>=75 40-4445-5455-6465-74>=75 MaleFemale Lifetime Prevalence p < 0.1 25%20%15%10%5%0% One-month Prevalence p < 0.001 30%25%20%15%10%5%0% MaleFemale Effect of Sex on the Prevalence of Insomnia by Age Years Years + * ***

18 A Telephone Survey in 2009 TSSM, 2009 n = 4,005

19 Prevalence of hypnotics abuse Focusing on zolpidem (Stilnox etc 18 kinds) NBHI (National Bureu of Health Insurance) –One million sampling data –From 1998 thru 2007 Zolpidem: –0.23% (1998) ----4.15% (2007), 18 times increase –Gender ratio: F:M=5.06:3.21 (1.6:1) –Age =65: 10.4% (2007) –Increased fold of zolpidem use from 1998 to 2007 15-fold (20-45 y/o), 16.8-fold (45-65 y/o) & 20-fold (>=65 y/o)


21 Dyssomnia Primary insomnia Restless leg Syndrome (RLS), Periodic limb movement d/o (PLMS) Narcolepsy, Sleep apnea Circadian rhythm sleep d/o Parasomnia Insomnia mixed with hypersomnia Sleep walking, Sleep terrors Nightmares, REM behavior Bruxism, NPD, enuresis Medical, psychiatric, & substance - induced sleep disorders DSM-IV




25 Narcolepsy prevalence 1/4000 (0.03-0.07%), M=F age onset: 10s to 20s, Dx: mid-life Abnormal manifestation of REM sleep intrusion into Wakefulness RBS (REM behavior disorder) Lately be along with narcolepsy DDX with idiopathic hypersomnia (IH), which has 1. Prolonged deep sleep, 2. naps often not refresh, 3. no evidence of cataplexy 4. May follow viral infection or head trauma ##60-100% 15-80% 17-80% 60-90% Legs/knees, jaw, slurred speech Dream-like /visual

26 Hallucinations in narcolepsy

27 Figure 64-1. Narcoleptic Doberman pinschers in the middle of a cataplectic attack. Note that eyes are open. Autosomal recessive forms of canine narcolepsy are due to mutations in the hypocretin receptor type 2 gene. Orexin deficiency hypothesis (loss of hypocretinergic neurons) (Orexin [hypocretin], promote wakefulness and inhibit REM sleep)

28 Pathophysiology of narcolepsy (1) loss of hypocretin-1 secreting cells in the hypothalamus (autoimmune-induced hypocretin deficincy) Hypocretin-1 levels are often decreased in narcolepsy with cataplexy but normal without cataplexy

29 Pathophysiology of narcolepsy (2) Electrophysiological signature REM sleep to occur within minutes of falling asleep Aberrnat monoaminergic regulation of cholinergic REM sleep mechanism Paucity of hypocretin (orexin) cells in 1. lateral nu of hypothalamus Decrease Wake-promoting system, 2,3,4,5 (PPN/LDTN). This leaves Cholinergic “REM sleep – on” cells uninhibited ---6.7 ---REM atonia

30 Sleep Switch: rapid transition From arousal to asleep & vice versa VLPO: ventrolateral preoptic nuclei - Inhibitory on arousal system and active during sleep - Damage on VLPO---chronic insomnia - Suppress VLPO --- awakening - receiving inputs from monoaminergic neurons - LC, TMN & Raphe nuclei, inhibit VLPO, are stabilized by orexin in the awake - Sleep switch has mutually inhibitory elements - In that, one side shut down the other side and diminish its own actions and result in abrupt change from awake to asleep In the sleep state: - VLPO inhibit orexin neurons and LC, TMN & Raphe nuclei Narcoolepsy - a problem with such a switch: rapid unwanted transitions from one state to the another can occur when it is unstable - Narcolepsy (2000) had few orexin neurons in the hypothalamus - Orexin neurons (hypocretin): active during wakeful- ness and reinforce the arousal system - Lost the stabilizing influence on the orexin neurons 1st

31 Neuronal degeneration of orexin neurons in lateral hypothalamus of a pt with narcolepsy vs. control

32 Narcolepsy Three - stage pathway for control of sleep Greater integration of multiple factors and greater flexibility in behavioral response SCN VLPO Few direct projections Orexin neurons Dorsomedial nu. of hypothalamus (DMH) 3rd system many physiological functions: eating, temp & cortisol cycle are affected.


34 Narcolepsy—REM sleep onset following light out, Dx by MLST, SOREMP Sleep disruption, repetitive awakening Decreased REM sleep latency And REM sleep onset


36 Mechanism of action of stimulants Modafinil: tx of sleep apnea patients with residual sleepiness, shift workers And narcolepsy

37 Mechanism of modafinil for waking effects Modafinil: Increase synaptic dopamine following Blockade of DAT and increase alpha – Adrenergic activity --- ultimately Produces downstream effects on Transmitters including glutamate and histamine DAT: dopamine transporter

38 Kleine-Levin syndrome Excessive sleep disorder with sleep- onset REM periods Symptoms –Hypersomnolence –Hypersexuality –Hyperphargia Adolescent onset and M > F


40 RLS with iron storage deficiency vs. controls ControlsRLS

41 Pathophysiology of Restless leg syndrome Hypothesis: dysfunction of the iron-dopamine connection Reduced iron In the area of red nu and sustantia nigra, which control motor system and the related dopamine dysfunction

42 PLMS during sleep initiation and maintenance PSG recording

43 RLS occurred when trying to fall asleep PSG recording in both legs

44 Obstructive Sleep Apnea in Psychiatry


46 Obstructive Apnea: A complete blockage of the airway despite efforts to breath. Notice the effort gradually increasing ending in airway opening. EKG Airflow Thoracic effort Abd. effort SAO 2

47 Intermittent Hypoxia

48 Cauter et al., 2008 Sleeplessness Trend

49 OSAS 患者之存活曲線 Kryger OSAS mortality Chest 1988 94 9


51 Circadian rhythm sleep disorder










61 Melatoniin secretion in the elderly Post-BLT n=10 Pre-BLT n=10 Mishima K., Okawa M. et al. J.Clin. Endocrinology Metab., 2001 Light therapy




65 3Ps model: Genetic or trait (anxiety & hyperarousal) Mood disorders Poor sleep habits (target with Cognitive behavioral Tx)

66 Perpetuating Factors Behavioral –Irregular sleep-wake schedule –Excessive time in bed –Sleep-incompatible activities –Excessive caffeine use, stimulating activities close to bedtime –Clock watching during the night Cognitive –Worry about sleep –Fear of not sleeping –Irrational beliefs concerning consequences of poor sleep

67 Persistence of Insomnia Over a 2-year Period (N=272) Good Sleepers Symptoms Syndrome 184 (68%) 88 (32%) 116 (43%) 63 (23%) 93 (34%) 100 (37%) 60 (25%) 104 (38%) Percentage Morin et al. 2006

68 Buysse DJ, et al. Sleep. 2008;31:473-80.  Strong association between pure insomnia and insomnia + depression  No association between pure insomnia and pure depression  Insomnia/c depression is an intermediate phenotype  Insomnia and Depression are Co-morbid Zurich Study

69  4,547 subjects recruited in 1978  591 subjects selected the 1 st stage screening  Follow-up in 1979, 1981, 1986, 1988, 1993, 1999  Cumulative prevalence of (1-month) insomnia: 24.4% Buysse DJ, et al. Sleep. 2008;31:473-80.

70 Zurich Study

71 Buysse DJ, et al. Sleep. 2008;31:473-80. Zurich Study

72 Insomnia: a risk for future psychiatric illness or comorbidity Once mood disorder is adequately treated, Tx must focus on insomnia if it is existing. Depression and insomnia –35 times of insomnia to develop depression than those without Bipolar disorders Anxiety and difficult sleeping Post-traumatic stress disorder and insomnia Sleep disturbance and psychosis Alcoholism and insomnia Borderline personality disorder

73 Sleep Hygiene


75 Moloney EM, et al. (2011). American Journal of Public Health.101;1423-33. Medicalized Sleeplessness

76 Richards G, SchochP, HaefelyW: Benzodiazepine receptors: new vistas. Seminars in Neuroscience 1991, 3:191-203 Functional binding sites on the GABA receptor

77 GABA-A receptor complex All US approved agents except remelteon Act by modulating the function of GABA-A Receptor complex, which are the medial Preoptic area (MPA) and ventrolateral preoptic Area of hypothalamus. Remelteon is agonist to act at melantonin type I and II Receptors in the SCN of hypothalamus. MT I receptor: decrease waking signal MTII receptor: alter clocklike functions of the SCN


79 Commonly Used BzRA Hypnotics Drug Scheduled Brand NameDosageDurationHalf-Life Zolpidem 4 Stilnox5-10 mgshort1.5-2.4 Zopiclone 4 Imovane3.75-7.5 mgshort5-6 Estazolam 4 Eurodin1-2 mgmedium8-24 Triazolam 3 Halcion0.125-0.25 mgshort2-3 Flunitrazepam 3 Rohypnol0.5-1 mgmedium10-20 Brotizolam 3 Lendormin0.25-0.5 mgmedium7 Nitrazepam 4 Mogadon5-10 mgmedium18-38 Midazolam 4 Dormicum7.5-15mgshort1.5-2.5 Nimetazepam 3 Erimin5mgmedium26 Flurazepam 4 Dalmadorm15-30 mglong40-100

80 Binding of BZD and Z drugs on GABA-A Alpha unit More selective in their binding to alpha isoform subtypes In Z-drugs than BZDs (benzodiazepines), which have wide range of pharmacological effects in addition to sleep Induction. Z-drugs have higher ratio of sleep/non-sleep effects as its selectively bind to Alpha -1 unit

81 BZDsZopicloneZolpidemZaleplon Sleep latency  Awakenings  TST  Stage 2  δsleep  REM sleep  Subjective quality  Impact on Sleep Architecture


83 Adverse effect of BzRA Adverse effects: –Daytime sleepiness (reaction time, recall, vigilance) –Risk of falls & hip fractures in the elderly –MVA rate increased –But did not show elevated mortality risk (cancer cohort) Discontinuation phenomena –Rebound phenomenon –Withdrawal: 40-100% with chronic use –Recurrence of insomnia –Abuse of BzRA---uncommon


85 The Vicious Cycle of Chronic Hypnotic Usage

86 如何好好睡眠 1. 認識睡眠 2. 了解睡眠 3. 把握好睡眠要訣 4. 減少導致失眠之外在因素 5. 如何放鬆自己、減少壓力 6. 了解安眠劑之使用概況 (1) 以最少、最有效之劑量 (2) 必要時使用 (as needed use) (3) 不完全排斥藥物,然而要掌控藥物,不能讓藥物控制你 7. 如有長期治療困難之失眠時,要尋找如何與失眠共處相互 生存 8. 光線治療之重要性

87 Take Home Message Insomnia is a symptom, and is also a disease. The reliability of insomnia diagnosis is unsatisfied. The validity of insomnia diagnosis remains questionable. More reliable and valid measures of insomnia are in need to avoid “medicalization” of sleeplessness. To study insomnia could make you sleepless. Lee, 2011


89 Effect of Triazolam on PSG in a 4-wk trial

90 RLS vs. medical condition in quality of life


92 Buysse DJ, et al. Sleep. 2008;31:473-80. Zurich Study


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