MANAGEMENT OF INSOMNIA IN THIS MILLENNIUM

1. MANAGEMENT OF INSOMNIA IN THIS MILLENNIUM Dr A V Srinivasan M.D, D.M., PhD (Neuro),FAAN,FIAN Emeritus Professor The TamilNadu Dr M.G.R Medical University Former Head- Institute of Neurology Madras Medical College, Chennai In Greek mythology, Hypnos was the personification of sleep; the Roman equivalent was known as Somnus. His twin was Thanatos ("death"); their mother was the goddess Nyx ("night"). His palace was a dark cave where the sun never shines. At the entrance were a number of poppies and other hypnogogic plants.

2. Sleep architecture revisited What is it & How is it relevant in Psychiatry and Neurology? Science is below the mind; Spirituality is beyond the mind

3. What is sleep? • Sleep is a physiological state of reduced sensory awareness and an absence of voluntary movements. • Sleep is necessary for life. • Sleep is also an essential component of good health (body development and restitution as well as mental health and well-being). It is also important for optimal cognitive functioning. A woman’s desire for revenge outlasts all her other emotions

4. Percentage of All People 50 40 30 20 10 0 0 2 4 5 6 7 8 9 10 Length of Sleep in Hours Total Sleep Requirement In order to be at your peak performance you need at least 8 hours of sleep.

5. Function of Sleep • Restoration and recovery • Sleep serves to reverse and/or restore biochemical and / or physiological processes degraded during prior wakefulness • Energy conservation • 10% reduction of metabolic rate below basal level • Memory consolidation • Thermoregulation • Homeostasis The world shall perish not for lack of wonders but lack of wonder

6. Awakenings Illustration of Normal vs. Insomnia Sleep Pattern Normal Sleep Pattern Onset Insomnia Sleep Pattern Onset

7. Normal sleep architecture NATURE, TIME AND PATIENCE are the 3 great physicians

8. Normal Sleep ArchitectureStages of sleep__________________________ 1. NREM Sleep A. Stage 1 B. Stage 2 C. Stage 3 D. Stage 4 2. REM Sleep Truth comes out of error sooner than that of confusion 10

9. Sleep Stages ___________________________ Wake 2/3 of life REM Sleep ~20% of night NREM Sleep ~80% of night Thought is the labour of the intellect Reverie is its pleasure 11

10. Normal Sleep Histogram Sequences of States and Stages of Sleep on a Typical Night Identification and Staging of Adult Human Sleep, L. Shigley, Sleep Academic Award

11. Stage 1 Body starts to relax ‘Falling asleep’ Stage 2 Brain slows ‘Stable, light sleep’ Stage 3&4 Body and tissue restored ‘Deep, restorative sleep’ REM Learning and memory consolidation ‘Dreaming sleep’ 20% 3-8% 45-55% 15-20% NREM 75-80% REM 20-25% Normal Sleep Stages 1 cycle = 80-100 minutes Adapted from Damien R.Stevens MD.Sleep medicine secrets.2004

12. Wakefulness, NREM, and REM

13. Importance of sleep architecture • Sleep architecture provides a useful means for quantitatively analyzing sleep. • It includes both macroarchitectural features (those derived from sleep staging) and microarchitectural features (those derived from waveform analysis). Architectural features can characterize: • sleep integrity and continuity • global sleep-stage structure • presumed underlying physiologic mechanisms

14. Neurochemical control of sleep-wake states

15. Neurochemical control of sleep-wake states • Dopamine • Adenosine • Nitrous oxide • Cytokines (IL-1, IL-6, TNF-α) • Prostaglandins • Hormones: melatonin, growth hormone, VIP NPY • Delta sleep-inducing peptide

16. Neurochemistry of Wakefulness & Sleep Aminergic Cholinergic Wake Fig. 2.1 aldrich Sleep REM Cholinergic Serotonergic Monoaminergic Histaminergic Basal Forebrain Thalamus Post. Hypothalamus Reticular Formation

17. Factors that affect sleep Social Isolation is in itself a pathogenicFactor for disease production • Age • Increased wakefulness during sleep period • Decreased Stage 3/4 NREM • Earlier timing • Greater daytime sleepiness • Sex (women have longer sleep, more Stage 3/4 NREM) • Timing: Sleep is best at night! • Illnesses, medications

18. 20 year old woman 71 year old woman Sleep in healthy young and older adults Motivation is the Spark that lights the Fire of Knowledge and fuels the engine of Accomplishment

19. Sleep stages across the life spanOhayon et al., SLEEP 2004; 27: 1255-73 Minutes Age (years)

20. Is there any difference between sleep and sedation? Mind is the great level of all things; human thought is the process by which human ends are ultimately answered - Daniel Webster

21. NREM/REM sleep Hypotonia/atonia Slow/fast eye movements Regular/irregular breathing, heart rate, BP SEDATION Analgesia Amnesia Obtundation of waking Anxiolysis Traits to define sleep and sedation Social Isolation is in itself a pathogenicFactor for disease production

22. Knowledge without action is useless; Action without knowledge is foolish Sleep v/s sedation • Sleep is reversible with sensory stimulation; sedation depresses sensory processing in the face of noxious physical &/or aversive psychological stimulation • Sleep disrupts mammalian temperature regulation during REM phase; Sedation can alter the relationship between body temp and energy expenditure • Nausea and vomiting are not associated with sleep; but can be positively correlated with sedation level.

23. Sleep architecture in neurological and psychiatric conditions A bad teacher complains; A good teacher explains; The best teacher inspires;

24. Effect of Sleep Stage in Epileptic patients on Interictal and Ictal Discharges Pure love ever gives. Never seeks

25. Seizure effect on sleep architecture • Seizures acutely alter the sleep-wake state. • The most prominent clinical features of this seizure effect are postictal somnolence and insomnia. • Patients with nocturnal seizures are subjectively and objectively sleepy on the day following a seizure. • Seizures or the postictal state produce pathophysiological changes in the CNS that result in sleep fragmentation and suppression of REM sleep. Individuals with partial or generalized seizures have less REM sleep on nights with seizures. “Anger Begins In Folly And Ends In Repentance”

26. Sleep in Patients With Depression • Primary sleep complaints1,3 • Difficulty falling asleep • Frequent nocturnal awakenings • Waking too early in the morning • Daytime fatigue • Effects on sleep architecture in depression1-3 • Prolonged sleep latency • Increased wake time after sleep onset (WASO) • Decreased slow wave sleep (stages 3 and 4) • Reduced REM sleep latency; prolonged first REM period 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev (DSM-IV-TR®). 2000:645-650. 2. Perlis M, et al. Biol Psychiatry 1997;42:904-913. 3. Benca RM. In: Principles and Practice of Sleep Medicine. 4th ed. 2005:1311-1326.

27. Sleep pattern in Alzheimer’s Disease • Sleep pattern in early stage: • Disruption in sleep-wake patterns, rhythmicity, • Increased amounts and frequency of nighttime wakefulness, • Reduction of slow-wave sleep - worsen with disease progression. • Sleep pattern in late stage: • Reduction of REM sleep, • Increased REM latency, • Alteration of the circadian rhythm resulting in daytime sleepiness. • Daytime napping and somnolence increase with disease progression.

28. Effect of drugs on sleep architecture “The Wise Man Before He Speaks , Will Consider Well What He Speaks

29. Effect of antidepressants on sleep architecture • Tricyclic antidepressants • Mostly produce sedation • Variation in the reported effects on sleep from TCAs. • Amitriptyline, trimipramine, nortriptyline, dothiepin and doxepin have all been associated with sedation, • Imipramine and desipramine are less likely to be linked with sedation, but have been associated with insomnia; • The evidence is less clear with clomipramine. Mayers AG et al. Hum Psychopharmacol Clin Exp 2005; 20: 533-559.

30. Effect of antidepressants on sleep architecture • SSRIs • SSRIs immediately suppress REM sleep, and continue to do so throughout treatment. • REM parameters return to normal once the SSRI is discontinued. • SSRIs block serotonin reuptake, but some also block noradrenaline reuptake. Both actions have been associated with REM suppression and sleep disruption. Mayers AG et al. Hum Psychopharmacol Clin Exp 2005; 20: 533-559.

31. Discipline Weighs ounces: Regret weighs Tons Effect of antidepressants on sleep architecture • Fluoxetine • Sleep was significantly less efficient, and nocturnal awakenings were significantly greater, with fluoxetine (20-40 mg) - Rush et al. (1998) • Fluoxetine significantly suppressed REM sleep • Fluoxetine (20 mg) was associated with less efficient, shorter and more disrupted sleep - Wolf et al. (2001) • Improvements in sleep latency and total sleep time were not marked for fluoxetine Mayers AG et al. Hum Psychopharmacol Clin Exp 2005; 20: 533-559.

32. Effect of hypnotics drugs on sleep architecture • Benzodiazepines • Being anticonvulsants, they tend to suppress synchronized EEG activity (such as slow waves) and confer some risk of seizure if abruptly withdrawn. • Barbiturates • Decrease REM and slow-wave sleep. • Non-BZD hypnotics. • Do not alter sleep architecture when taken at therapeutically recommended doses. Some people feel the rain; Others just get wet

33. Stage 0 Stage 0 REM REM Stage 1 6.64% Stage 1 10.50% 7.27% 16.39% 19.02% 6.26% 15.81% Stage 4 11.22% Stage 4 44.48% 8.51% 46.23% 7.65% Stage 3 Stage 3 Stage 2 Stage 2 Stilnoct®Preservation of Sleep Stages Placebo Stilnoct Opinion is ultimately determined by the feelings and not by the intellect N=36 Data on file. Sanofi-aventis.

34. Sleep Disorders International Classification of Sleep Disorders (ICSD-2) (1) insomnias (2) sleep-related breathing disorders (3) hypersomnias not due to a breathing disorder (4) circadian rhythm sleep disorders (5) parasomnias (6) sleep-related movement disorders (7) other sleep disorders, and (8) isolated symptoms, apparently normal variants, and unresolved issues. It is the province of the knowledge to speak and it is the privilege of the wisdom to listen - Hodly’s

35. Insomnia Difficulty in initiating sleep and staying asleep Waking up earlier Poor quality sleep, non restorative. Subjective Day time impairment (RDC-AASN) The meek shall inherit the earth - but not its mineral rights

36. Etiology Primary Secondary Medications Psychiatric Medical Sleep Disorders A Man Of Words And Not Of Deeds Is Like A Garden Full Of Weeds

37. Drugs SSRI’s & SNRI’s Alpha and beta blockers Diuretics Decongestants Stimulants Steroids, thyroid harmones What is mind no matter What is matter never mind

38. Psychiatric and Sleep disorders Mood & anxiety disorders Circadian rhythm disorders Parasomnias Apneas Movement disorders ''When Beauty Fires The Blood; Love Exalts The Mind"

39. Hypersomnias Excessive day time sleepiness Interfering with day time activities, productivity, enjoyment Reflects insufficient sleep, disrupted sleep, primar sleep disorder Experience : “Yesterday’s Answer To Today’s Problems”

40. Diagnosis Detailed medical and sleep history Snoring or apnoea Restlessness, jerking Hypnogogic or hypnopompic hallucinations Sleep paralysis, cataplexy Automatic behavior Teachers are reservoirs from which, through the process of education, the students draw the water of life

41. Narcolepsy Excessive day time sleepiness (EDS) Sedentary and active pursuit's Short and refreshing Followed by recurrent somnolence Ranging from mild to disabling Name and form are destroyed in the sands of time

42. Cataplexy Unique Paroxysmal episodes of weakness Triggered by emotions Secs to Min Can be localized Consciousness and respiration not affected. Time and tide wait for no man; And sins and sorrows are also swallowed in time

43. Develops years after EDS Frequency varies Adolescence, young adulthood Narcolepsy with and without cataplexy Loss of hypocretin – 1 secreting cells Every man is a volume if you know how to read him

44. Narcolepsy – non obligate manifestations Sleep paralysis – muscle atonia at interface between sleep and wakefulness; for few minutes. Hypnogogic hallucinations brief, Sec to Mins, dream-like vivid and distressing Automatic behavior Purposeful/inappropriate with impaired recollection of the activities. Being ignorant is not so much a shame as being unwilling to learn

45. Other Hypersomnias Recurrent hypersomnias Recurrent hypersomnias Kleine – Levin syndrome Menstrual associated Idiopathic hypersomnias With long sleep time Without long sleep time Beauty lies in the eyes of the beholder

46. Parasomnias Include abnormal movements, behaviors, emotions and automatic activities. Intrusion of sleep and wakeful state into one another with CNS activation. Not a unitary phenomenon. The secret of walking on water is knowing where the stones are

47. Parasomniasis Disorders of arousal – NREM sleep – confusional arousal sleep walking sleep terrors REM sleep – RBD Isolated sleep paralysis Nightmares Others – enuresis eating disorders etc Future Medicine – Scientific determinism or humanism

48. RBD – REM Sleep Behavior Disorders Prevalence of 0.5%; 90% Men Above 50 years 25% with PD, OPCA, DCBD Complex motor activity during REM Augmentation of EMG tone during REM sleep Toxic/metabolic disorders

49. RBD During second half Abnormal brain stem control of medullary inhibitory regions Cat models- locus ceruleous adjacent lesions SPECT – decrease striatal dopa innervations decrease dopa transportation Withdrawal of alcohol, sedatives Hypnotics TCA, SSRI, MAOI, cholinergics The sign wasn’t placed there By the Big Printer in the sky

50. Sleep-Related Movement Disorders- Restless Legs Syndrome 5-15% - healthy people 15-20% - uremia 30% - R.A High prevalence in West Low in South & S.E Asia A open foe may prove a curse ; but a pretended friend is worse