UPDATE ON THE EVALUATION TREATMENT OF INSOMNIA

1. UPDATE ON THE EVALUATION & TREATMENT OF INSOMNIA Eben L. McClenahan, M.D., M.S., Medical Director Region III – Office of Mental Health Louisiana State Department of Health & Hospitals Assistant Clinical Professor Department of Psychiatry & Neurology Tulane University School of Medicine – New Orleans

3. Sleep Stages (continued) NREM: Stage 1 – transition to sleep with Theta waves Stage 2 – light sleep Stages 3 & 4 – Delta slow-wave sleep

4. Sleep Stages (continued) Rapid Eye Movement (REM) Sleep: Also known as ‘paradoxical sleep’ because while a person’s body is immobile with their muscles being paretic, areflexic, & flaccid, yet there is increased pulse, blood pressure, intracranial pressure, & cerebral blood flow - and also, in men, erections – and there is heightened incidence of myocardial infarctions & ischemic cerebrovascular accidents – dreams occur, via 2 components tonic & phasic

5. Normal Course of Sleep,and some terminology Usually fall asleep in 10-20 minutes (interval called Sleep Latency) Normal individuals enter NREM & pass through the 4 stages, and this form of sleep predominates during early night REM periods occur 4-5 times nightly, 1st after ~90 minutes (interval called REM Latency), & become progressively longer, and when REM is greatest the body’s temperature reaches its nadir, and the final REM period can merge with awakening – eye movements generated by vestibular nuclei in the Pons of the brainstem

6. Sleep Across the Lifespan 1st NREM-REM cycles detected in 20 week old fetus – neonates sleep 16-20 hours/day with ~ 50% in REM – as we mature and age, we have: less total time sleeping & less dreaming - elders have: shorter nighttime sleep (& reduced slow-wave NREM sleep) fragmented by awakenings, also phase advance such that they go to bed and also awaken earlier [not necessarily a sign of MDE], & less Melatonin

7. A Bit of Neurochemistry Serotonin: facilitates REM and shorter sleep latency and reduced nocturnal awakenings Acetylcholine: associated with REM sleep Hypocretin-1: excitatory modulation, with connections to adrenergic, dopaminergic, cholinergic, and serotonergic systems Dopamine: arousal, alerting, wakefulness Melatonin: regulates sleep/wake cycle via circadian clock in hypothalamus

8. A Bit of Neuro-physiology/anatomy Suprachiasmatic Nucleus (SCN) in the Hypothalamus – circadian clock & the sleep/wake switch Thalamus – cortical activation, EEG synchronization Brainstem – ascending cortical activation (Reticular Activating System), REM source Locus Ceruleus – 80% of Norepinephrine

9. Circadian Rhythms The Suprachiasmatic Nucleus (SCN) is the biological clock, located above the optic chiasm The SCN receives information about light via the Retinohypothalamic Tract, then has efferent sympathetic pathway to the Pineal Gland (aka ‘The Third Eye’), resulting in synthesis & secretion of Melatonin, which then provides negative feedback to the SCN during the day’s dark period (called scotoperiod) - Melatonin in Humans, New England Journal of Medicine, 1997

10. Circadian (continued) Light acutely stops Melatonin production, and this can occur between dusk & dawn as with the graveyard shift – the converse does not hold as darkness imposed from dawn to dusk cannot increase Melatonin while the SCN acts to turn off Melatonin production for about 12 hours during this daytime period For many animals, the changing duration of the scotoperiod across the year has corresponding changes in Melatonin, yielding seasonal cues to regulate migration, hibernation, & estrous

11. Why do we spend 1/3 of our existence sleeping? Sleep that knits the raveled sleeve of care - Shakespeare

12. Why asleep? (continued) Consolidating memories, slow-wave learning, & elaborating brain plasticity “Per chance to dream?” (Shakespeare) Lest consequences of sleep deprivation!

13. Memory Consolidation While we sleep, there is an active process such that memories are encoded, stored, and even enhanced A memory is considered Consolidated when in the absence of rehearsal it has become sturdy enough to resist disruption from any new learning, perceptions, thoughts, actions

14. Consolidating Memory (continued) Procedural learning – re: the category of memory which includes perceptual & motor skills and consolidating occurs during the deepest Slow-Wave Sleep (Stages 3 & 4 of NREM) A memory integrates into the mind’s fabric, and ceases depending solely on the Hippocampus, rather it distributes across cortex, & links webs of associations, knowledge, & related memories

15. Consolidating Memory (continued) PET & fMRI studies show that the brain has a propensity for Plasticity, whereby encoding new information entails structural brain changes at the level of individual synapses, between circuits, and over different regions Learning is offline – the brain continues to learn even when no longer consciously practicing

16. Consolidating Memory (continued) This learning/consolidation is all-or-nothing 36 hours awake robs people of much of their ability to perform these functions Caffeine is no substitute QUESTION: Can sleep deprivation cause some functional lesion in the Hippocampus, and if so is it reversible?

17. Consolidating Memory (continued) Emotional processing, eg. ‘sleeping on a problem’ ? role of the Amygdala: which is principally involved in the encoding & retrieval of emotional memories, and also the Amygdala displays higher activity during REM than wakefulness while maintaining reciprocal relationship with the Hippocampus

18. To Dream? Dreams form via interplay of tonic & phasic REM events – phasic REM triggers visual images & during intervening tonic REM periods associations to these images occur, & this image-then-association sequence facilitates visual components being woven into a dream story within the REM episode – dreams often herald important meanings at interpretation

19. To Dream? (continued) One Famous Dream: Friedrich August Kekule von Stradonitz – famous for his elucidation of the structure of Benzene (in a 6 Carbon atom ring configuration) after he dreamt of a snake swallowing its tail [symbol known as Ouroborus] – of the first 5 Nobel Prizes in Chemistry, his students won 3 (in 1901, 1902, & 1905)

20. To Dream? (continued) Christian Biblical references: In the New Testament it is because of a dream that Joseph accepts the pregnancy of Mary as being of divine origin – the instructions to flee into Egypt and then later to return are also sent by dreams

21. To Dream? (continued) Role of the dream in psychotherapy: Serves as an instrument as qualitatively reliable as any brain scan, psychometric testing, or measured neurotransmitter level ? re: affective tone, diagnostic assessment, self-representation, conflict, defenses, transference, problem-solving, & decision-making* *J. Psychotherapy Practice & Research, Glucksman, 2001

22. Sleep Deprivation Our 24/7 lifestyle can be deleterious Trying to push through the night and stifle a yawn, yet that yawn is the first sign that you’re not so awake as you might like to think – after 18 hours in the absence of sleep, your reaction time slows from ¼ of a second to ½ of a second, and then becomes still longer

23. Deprived of Sleep (continued) One starts experiencing several bouts of ‘micro-sleep’ – and so, while driving you zone out for say 20 seconds and drift out of your lane, or if studying late then you find yourself rereading the same passage – thus your reaction time becomes roughly equivalent to a person with a blood alcohol level of 0.08, sufficient to get you arrested in 49 states

24. Deprived of Sleep (continued) Sleep is vital - extraordinary adaptations Zebras on the savanna require vigilance of awake herd members in order to sleep safely in the presence of predators Dolphins & other cetaceans are able to have one brain hemisphere sleep at a time, to allow ongoing motion and continued respiration

25. Deprived of Sleep (continued) Charles Augustus Lindbergh, in 1927, in his Spirit of St. Louis, during his 1st solo Atlantic crossing from Long Island to Paris, experienced visual hallucinations which remitted with recovery sleep There is a 10% increase in MVA’s following switching to daylight savings when the day is shortened by 1 hour

26. Deprived of Sleep (continued) Mood disturbance with irritability, transient paranoia, disorientation, performance deficits, severe fatigue or hypomania – all sequelae of prolonged sleep deprivation Chronic sleep deprivation may reach a point at which the very ability to catch up on sleep is damaged, such that what’s lost is lost Bodes ill for physicians, soldiers, et al trying to acquire new information while sleep-deprived

27. Insomnia – what’s that about? It’s a symptom, not a stand alone diagnosis, & an estimated 30-50% of general population afflicted, ~10% chronic Acute: difficulty sleeping a few nights over a couple of weeks, often from a stressor Chronic: difficulty sleeping at least 3 nights per week for 1 month or more & interfering with daytime functioning

28. An Insomnia Typology Difficulty falling asleep Difficulty staying asleep Waking too early Non-restorative poor quality sleep

29. Insomnia Mechanisms Disorders of circadian rhythms Disordered homeostatic drive for sleep Disordered sleep mechanisms Dyssomnias & Parasomnias Disordered arousal mechanisms Medical & psychiatric disorders Substance/medication-induced disorders

30. Evidence of Hyperarousal in Primary Insomnia Increased global cerebral glucose metabolism on PET During sleep, EEG shows decreased Theta & Delta wave activity Increased 24-hour metabolic rate Higher levels of secretion of both Adrenocorticotropin & Cortisol

31. Sleep Evaluation Measures Polysomnogram (PSG): gold standard measures of cerebral activity (EEG); ocular movements; chin & limb & other muscle movements (EMG); vital signs; and oxygen saturation Epworth Sleepiness Scale (ESS): assesses fatigue (anergy) during typical daily activities Multiple Sleep Latency Test (MSLT): PSG monitoring re: rapidity of sleep onset (with naps apart by 2 hour intervals) & presence of REM ? propensity to readily fall asleep = sleepiness

32. Sleep Evaluation (continued) Take a history re: falling & staying asleep, early awakening, quality of sleep, EDS Also interview patient’s bed partner Review lifestyle, habits, medications, illnesses, sleep hygiene, stressors Patient to keep a sleep diary – record bedtime, number of awakenings, sleep latency, naps, substances used, irritability, estimate of amount of sleep obtained

33. Sleep Disorder Classification Dyssomnias are disorders of initiating & maintaining sleep, with Excessive Daytme Somnolence (EDS) – 3 types: intrinsic, extrinsic, and circadian Parasomnias - characterized by abnormal behavior or physiological events at specific stages or sleep-wake transitions, involving inappropriate activation of autonomic & motor systems – usually with both normal restful sleep & REM Latency, and without EDS

34. Dyssomnias - Intrinsic Primary Insomnia – Psychophysiologic and Idiopathic Narcolepsy Sleep Apnea Periodic Limb Movements Restless Legs Syndrome

35. Dyssomnias - Extrinsic Inadequate sleep hygiene Environmental sleep disorder Secondary to toxins & substance dependence

36. Dyssomnias - Circadian Time zone changes (jet lag) Shift work Changes in sleep phase – advanced & delayed

37. Parasomnias Sleep Terrors Somnambulism Nightmares REM Sleep Behavior Disorder Jactatio Capitis Nocturna Bruxism Enuresis

38. Medical & Psychiatric Causes of Sleep Disorders Major Depression Bipolar Disorder Seasonal Affective Disorder PTSD Alcoholism Dementia (& Sundowning) Parkinson’s Disease Epilepsy Pain Syndromes Cluster Headaches Insomnia in Menopause Fatal Familial Insomnia Exploding Head Syndrome

39. Primary Insomnia – Idiopathic/Psychophysiologic Conditioned behaviors – behavior not conducive to sleep becomes associated with bedroom – eg. a married couple when arguing retreats to bedroom as sanctuary from children – or once in bed watching clock incessantly to see how long one has been unable to fall asleep ?ergo, reserve bedroom for sleep & sex exclusively

40. Primary Insomnia (continued) Misperceptions and erroneous beliefs – patients unable to assess their sleep efficacy and whether they have been awake or asleep Unrealistic expectations “I have to sleep 8 hours at night or the next day will be ruined” Problems with sleep hygiene (eg. naps)

41. *Hey, What’s Wrong with Naps?!(brief hiatus) Naps act to diminish the homeostatic drive to sleep, thus interfere with night rest However, napping is acceptable as one single ~30 minute nap per midday for elders, who have sleep fragmentation, as well as diminished total & NREM sleep *humorous satirical article: The Art of the Nap, American Scholar, 1995

42. Primary Insomnia (continued)Treatment Strategies *(Nonpharmacologic) Cognitive Restructuring Therapy Relaxation Skills Training Stimulus Control Rx Sleep Restriction Rx Sleep Hygiene * pharmacotherapy discussed later

43. Stimulus Control Don’t engage in obsessive clock watching Observe a regular wake time, regardless of duration of sleep If unable to sleep after 15-20 minutes, then go to another room to read and engage in quiet activities, and only return to bed when sleepy

44. Sleep Restriction Reduce time in bed to estimated total sleep time (minimum, 5 hours) Increase time in bed by a 15 minute increment per week when estimated sleep efficiency [ratio of time asleep to time spent in bed] is at least 90%

45. 10 Commandments of Good Sleep Thou shalt not stay in bed too long Thou shalt go to bed only when sleepy Thou shalt avoid daytime naps Thou shalt avoid stimulants after lunch Thou shalt not take evening toddies Thou shalt observe a regular sleep-wake schedule

46. 10 Commandments (continued) 7) Thou shalt exercise regularly, but not too close to bedtime 8) Thou shalt not go to bed hungry 9) Thou shalt not watch TV, use laptop, knit, read, etc. in one’s bed 10) Thou shalt reduce noise in a bedroom kept at a comfortable temperature

47. NarcolepsyClassic Symptom Tetrad EDS with sleep attacks (naps not restorative) Sleep Paralysis – at sleep/wake interface Hypnagogic &/or Hypnopompic Hallucinations Cataplexy – strong emotion (often positive, eg. laughter) elicits loss of all striated muscle tone (except diaphragm) – similar physiological mechanisms in REM sleep atonia* *Lancet, 2007

48. Narcolepsy (continued)Additional Diagnostic Features Very short REM Latency MSLT – patient is placed in dark quiet room, & asked to fall asleep ? test is considered abnormal if patient falls asleep within 8 minutes Hypocretin-1 concentration in CSF – very high positive predictive value if lower than 110 ng/L

49. Narcolepsy - Treatment Xyrem [Sodium Oxybate (salt of Gamma Hydroxybutyrate)] – ensures good nighttime rest, and treats both EDS and cataplexy – two doses given, one at bedtime & the other 4 hours later Modafinil [Provigil] – alerting & performance-enhancing – two doses, one in AM and the other at Noon

50. Sleep Apnea Central – also called Odine’s Curse – poor CNS ventilatory effort and Cheyne-Stokes irregular breathing - bulbar poliomyelitis & lateral medullary infarctions Obstructive – also called Pickwickian Syndrome – obesity is a major risk factor – loud snoring, and then breathing ceases for as much as 30 seconds or more, with resuscitative resumption of breathing – Rx with CPAP (nasal continuous positive airway pressure) and daytime activating antidepressant (eg. Prozac)

51. Sleep Apnea (continued) Both varieties can produce severe hypoxia (especially during REM muscle atonia), with arterial blood oxygen desaturation as low as 40% - risk of cardiac arrythmias, & both pulmonary & systemic hypertension Symptoms include: headache, intellectual impairment, depression, irresistible urges to nap (Dickens’ Joe in The Pickwick Papers)

52. Periodic Limb Movement Disorder(aka Nocturnal Myoclonus) Stereotyped, brief, regular [in episodes of 10 minutes to a few hours] dorsiflexions of the feet, occurring primarily during NREM sleep Can be associated with apnea, RLS, uremia, antidepressants, & medication withdrawal Rx with BZD’s, and dopamine agonists can be of some benefit

53. Restless Legs Syndrome Random, irregular movements of feet & legs during sleep, and to lesser extent during wakefulness – associated with aching & burning sensations – movements as if pacing, shuffling, bicycling About 1/3 of patients have no underlying condition – can occur with diabetic neuropathy, during pregnancy, & in iron deficiency Rx with dopamine agonists and tricyclic antidepressants, also opiates

54. Circadian Rhythm Disorders The internal sleep-wake cycle does not match desired sleeping & waking times (eg. blind individuals are not entrained by external stimuli [zeitgebers = ‘time givers’]) Advanced Phase – go to bed early & awaken early – common in elders – if delay bedtime, still awaken early (role for Melatonin & light therapy) Delayed Phase – individual never falls asleep until late [prolonged sleep latency] into night (a ‘night owl’) then sleeps through the AM ? chronotherapy Rx gradually shifts the person’s sleep/wake cycle to a more adaptive schedule

55. Jet Lag Rapid traversing of 2 or more time zones leads to insomnia, EDS, and also changes in digestion & autonomic behavior Going East to West is easier as travelers can more easily postpone (delay) their night’s sleep, than fall asleep earlier (advance) – a helpful strategy is to shift the sleep-wake cycle to their destination’s day-night schedule before the trip (helps re: adaptation of athletes & sports teams)

56. Jet Lag (continued) Also beneficial is exposure to daylight upon one’s arrival at the destination & taking Melatonin Regarding the most taxing West-to-East flights, one can take a hypnotic agent (eg. Benzodiazepine) to advance the sleep schedule to conform to the new time zone

57. Shift Work Disorder Working the ‘graveyard shift’ or continually changing [associated with higher rates of divorce & substance abuse] schedule between days & nights One consequence is less Melatonin (the hormone of darkness) synthesis and secretion – Melatonin is an important antioxidant, scavenging oxygen free radicals, thus protecting against cancer Best to use public transportation [or to carpool with an alert driver] for safer commuting

58. Shift Work (continued) Difficult to adjust, especially if employing old familiar schedule on weekends Strictly applying all sleep hygiene principles can be quite helpful Provigil may assist re: on-the-job alertness Chronotherapy helps - delay (with coffee, activities, light) sleep onset 30-60 minutes each night and ultimately by < 24 hours & via effort then maintain the new schedule

59. Major Depression PSG demonstrates: reductions in total & slow-wave (NREM stages 3 & 4), and increased awakenings – also REM has shorter latency, followed by abnormally long intense REM period, then subsequent REM periods in relatively quick succession, leaving the latter half of the night virtually devoid of REM For some patients, partial deliberate sleep deprivation (albeit impractical) may reduce symptoms (Sx’s) as effectively as antidepressant medication

60. Major Depression (continued) The body’s temperature nadir and Cortisol excretion occur earlier, thus there is forward displacement of the circadian pattern, constituting a phase advance, and this can result in early AM awakening with resultant inability to resume sleep – depressed patients skip into the middle of normal sleep and of the neuroendocrine cycle – one of the last Sx’s to improve

61. Seasonal Affective Disorder (SAD) Hypothesis: do circadian rhythms drift later with the later dawn of winter, thereby acting as a cue to susceptible individuals to become depressed & exhibit phase delay at this time of year Treatment often includes antidepressant Light exposure therapy, a standard of care, is optimal at AM awakening

62. SAD (continued) All of which gives rise to questions: Does light have a specific antidepressant effect other than phase shifting? 2) What might we apply of that which we learn from SAD to better understand the other affective disorders?

63. Alcohol (EtOH) Dependence Associated with insomnia & EDS First ½ of night: short sleep latency, less REM sleep, & increased slow-wave sleep, tantamount to collapsing into stupor In second ½ of night: increased REM and awakenings, as though emergent delirium Net effect: decreases both total sleep time & slow-wave sleep EtOH withdrawal produces REM rebound

64. Dementia Increased awakening - decreased REM & slow-wave sleep - nocturnal wandering & delirium - deficits from neurotransmitter loss (including Melatonin & Serotonin) Sundowning - at dusk: loss of orientation with confusion, hallucinations, fears, delusions, & even combativeness Incidence increases among demented patients during winter when there is less natural light Interventions: environmental (night-light, nap-restriction); interpersonal reassurances; short-term antipsychotic medicine; treatment of underlying infection, electrolyte disturbance, & toxic medication side-effects/interactions

65. Parkinson’s Disease While tremor, rigidity, & dyskinesias disappear, at night, yet thought disorders and hallucinations (especially visual) arise Iatrogenic problems in as much as secondary to dopaminergic medicines [however, Mirapex (Pramipexole) facilitates somnolence] and so these must be carefully managed Comorbid intrinsic depression also interferes Eschew neuroleptics which exacerbate disease

66. Epilepsy Nearly ½ of patients with primary generalized epilepsy have predominantly nocturnal Sz’s during the 1st portion of the night’s sleep mostly in NREM stages 1 & 2 Sleep deprivation can precipitate Sz’s Antiepileptic medicines at therapeutic levels reduce arousals and act to increase slow-wave sleep

67. Cluster Headaches About 50-75% occur at night, with episodic awakening to paroxysm of icepick-like periorbital stabbing pain & lacrimation in the eye on the affected side (also with occasional partial Horner’s pupillary miosis & eyelid ptosis), often in a period of REM sleep Circadian influence (re: periodic recurrence) inferred from low levels of Melatonin, Cortisol, Prolactin, & Testosterone during attacks Lithium is Rx of choice when tolerated - also Prednisone acutely as needed

68. Fatal Familial Insomnia Inherited progressively severe insomnia -refractory to treatment - beginning around age 50 Begins with amnesia, poor concentration – later with elevated catcholamines, tachycardia, hyperhidrosis, myoclonus, ataxia – ultimately fatal (in 6 - 36 months) Closely related to Creutzfeldt-Jakob’s dz – there is evidence of thalamic atrophy

69. Exploding Head Syndrome Once called “snapping of the brain” Abrupt flashing lights and noises within the brain, not related to any particular stage of sleep, and beginning around age 50 Lasting only seconds, and is truly quite terrifying to patients notwithstanding the absence of any pain

70. Insomnia in Context of Menopause Not only the result of the considerable disruption from nocturnal hot flashes Not trivial as insomnia in menopausal women is associated with greater incidence of MI’s & CHF Affects ~40 % of women – reduced sleep, early awakenings, EDS, irritability, & mood lability Likely related to decreased Serotonin secondary to decreased Estrogen Rx: CBT, HRT, Clonidine, SSRI’s, BZD’s

71. Pharmacotherapy of Insomnia CBT just as good in many cases, and even better re: reducing sleep latency* - can assist chronic users of BZD’s to either discontinue or reduce usage** What would be the ideal hypnotic: rapid onset, maintaining concentrations above the minimal effective amount throughout course of sleep and even increasing over the night to compensate for gradual reduction in homeostatic drive, then with level reaching nadir just prior to awakening (lest hangover, EDS, memory & motor problems) * Am. J. Psychiatry, January 2002 ** Am. J. Psychiatry, February 2004

72. Many Medications Disrupt Sleep Beta blockers (interfere with Serotonin & Melatonin) Asthma medicines ADHD medicines Antidepressants (often depress REM, thus there is REM rebound at discontinuation) Hormones (corticosteroids, thyroid)

73. Stimulants Some Common Sources Now-a-days: Coffee: a cup of Joe with ~100-150 mg of caffeine = 1 mg of amphetamine Red Bull: 250 mL = 80 mg of caffeine Baker’s Chocolate: 1 oz = 26 mg of caffeine

74. Stimulants (continued) Modafinil – not chemically related to amphetamines – well tolerated & with low abuse potential (Schedule IV), & without tachyphylaxis – promotes wakefulness by inhibiting release of GABA at certain brain sites and enhances release of the alerting monoamine Histamine and binds to the Dopamine Reuptake Transporter – has no effect on cataplexy

75. Dietary/Herbal Sleep Preparations(pea-shooters in the armamentarium) Mostly: L-Tryptophan, Valerian, & Kava-kava L-Tryptophan: precursor of Serotonin, a substrate for Melatonin – in milk (doesn’t need to be warmed) & turkey – FDA has limited availability after > 1,500 cases of Eosinophilia Myalgia Syndrome with at least 37 deaths in 1989

76. Dietary/Herbal (continued) Valerian (derivative of Valeriana officinalis plant): mechanism may be via inhibiting GABA reuptake or inhibiting postsynaptic potentials through activation of adenosine receptors in cortical neurons – in one study, little difference vs. Benadryl* - inhibitor of CYP3A4 – withdrawal when extensive use, similar to that seen with BZD’s – risk of hepatotoxicity & delirium * Sleep, 2005, 28: 1465-1471

77. Dietary/Herbal (continued) Kava-kava: from root of Piper methysticum plant endogenous to Western Pacific, and used as hypnotic & anxiolytic – banned in many countries due to reports of serious hepatoxicity ______________________ Others: Melatonin (OTC), Chamomilla (Sleepy-Time Tea), & Passiflora

78. The Atomic Bomb for Insomnia Chloral Hydrate (neither BZD nor Barbiturate) – today seldom used re: development of tolerance, hepatic & myocardial tissue damage, nightmares, ataxia, rare paradoxical excitement, hangover, GI irritation – also narrow therapeutic index with risk of death due to respiratory depression – also withdrawal Sx’s of delirium & Sz’s (seizures)

79. Seroquel & Zyprexa Goodness gracious, please don’t prescribe these for sleep problems, lest you harm: your patients by inviting metabolic syndrome, and yourself with ensuing litigation!

80. Benzodiazepines (BZD’s) Many vexing side effects to consider: Rebound insomnia upon D/C – also alter sleep architecture: decreased REM & slow-wave sleep Short-acting: anterograde amnesia especially with Triazolam (Halcion), and can over time sensitize the HPA axis (Hypothalamic-Pituitary-Adrenal axis) leading to anxiety & need for dosage increase Long-acting: associated with increased risk of falls & hip fractures in older patients

81. Sodium Oxybate Acts to hyperpolarize postsynaptic GABAB receptors located on thalamocortical neurons, and then induces pacemaker rhythms to form basis of slow-wave sleep, while it inhibits release of activating neurotransmitters (Norepinephrine, Dopamine, & Acetylcholine), thus establishes physiological conditions resembling natural sleep state – inhibits cataplexy Sodium load may exacerbate hypertension in some vulnerable individuals

82. Newer Agents(Ambien, Sonata, Lunesta)[Schedule IV Controlled] Ambien (Zolpidem): minimal alteration in sleep architecture, and without rebound insomnia at D/C – should take only if able to get full night’s sleep before resuming activity– similar to Triazolam in causing impaired short-term memory that is reversible by Flumazenil – concerning side effects (SE’s) include nightmares & amnesia - $4.02/tablet (5 & 10 mg)

83. Newer Agents (continued) Sonata (Zaleplon): very short 1 hour ½-life used prn for sleep-onset insomnia, and can be used as last resort in early AM with at least 4 hours left to dedicate to sleep – SE’s include anxiety, increased menstrual pain, tingling/numbness, rash, & daytime poor concentration - $2.79/tablet (5mg) [$3.87 for 10 mg tablet]

84. Newer Agents (continued) Lunesta (Eszoplicone): FDA approved for chronic use, with no tolerance over 6 month interval – SE’s include bitter metallic taste, cold symptoms, decreased libido, increased menstrual pain, vivid unusual dreams, painful gynecomastia in males - $3.75/tablet (3 mg)

85. Benadryl (Antihistamine) & Trazadone Diphenhydramine: for certain individuals paradoxical excitement results from use – risk delirium in elders – tolerance develops rather quickly – may decrease REM sleep Trazadone: residual daytime sedation is common – SE’s of priapism, orthostatic hypotension, and also the Serotonin Syndrome* if taken with SSRI * J. Clin. Psychiatry, 2004

86. Clonidine & Prazosin re: PTSD These generally ablate nightmares via lowering of adrenergic tone & arousal Can combine with Imagery Rehearsal Rx* Prazosin reduces light sleep (a time when PTSD nightmares arise) and normalizes REM, and also reduces secretion of corticotropin-releasing hormone** * JAMA, August 2001 ** Am. J. Psychiatry, February 2003

87. Ramelteon (Rozerem) Not a controlled substance – no abuse liability – no cognitive or motor impairment at up to 20 times recommended dose – no associated alterations in sleep architecture $2.89/tablet (8 mg) Available on many health insurance plans (including United Healthcare, Humana, Coventry, & Tricare) No rebound insomnia or withdrawal upon D/C

88. Ramelteon (continued) Selective MT1/MT2 receptor agonist: - MT1: promotes sleep by inhibiting SCN - MT2: chronobiotic, phase advance - several times greater affinity than ingesting OTC Melatonin Negligible affinity for: BZD/GABA, Histamine, Dopamine, Acetylcholine, Serotonin, & Opioid receptors

89. Ramelteon (continued) Due to short ½-life (1-2.5 hours) repeated once per day dosing does not appear to result in accumulation, thus can take long term Improves sleep latency, total sleep time, and sleep efficiency Ramelton 16 mg indistinguishable from Placebo re: mood, concentration, & alertness [per Digit Symbol Substitution Test, Visual Analog Scale, immediate & delayed memory recall tests]

90. Ramelteon (continued) Treatment of choice for insomnia in context of substance dependence 4 Rhesus monkeys given Ramelton (10.0 mg/kg) did not choose to substitute it for BZD, and over 1 year neither positive reinforcing nor withdrawal effects were observed 14 adults with Hx sedative abuse and taking up to 60 mg Ramelton [vs. Placebo, vs. Triazolam (0.25-0.75 mg)] showed no significant abuse potential per subjective measures

91. Ramelteon (continued) Few Caveats: Mild Prolactin elevation, mostly in females Avoid combining with Luvox (strong CPY1A2 inhibitor) as can dramatically increase Ramelton concentration – only absolute contraindication Do not use in significant hepatic impairment ______________________________ No significant pharmacokinetic interactions with Digoxin, Warfarin, Omeprazole, & Theophyline

92. Ramelteon (continued) Salient References: Johnson, MW, et al, Ramelteon: A Novel Hypnotic Lacking Abuse Liability & Sedative Adverse Effects, Arch. Gen. Psychiatry, 2006, 63: 1149-57 Bellon, A, Searching for New Options for Treating Insomnia: Are Melatonin & Ramelteon Beneficial?, J. Psychiatric Practice, 2006, 12(4): 229-43 Rozerem (Ramelteon) in the Management of Insomnia, U.S. Pharmacist, April 2006 Roth, T, et al, Effects of Ramelteon on Patient-reported Sleep Latency in Older Adults with Chronic Insomnia, Sleep Medicine, 2006, 7(4): 312-18

93. Ramelteon (continued)[further references] Ramelteon: Profile Report, CNS Drugs, 2005, 19(12): 1057-67 France, C, et al, Ramelteon Does Not Have Benzodiazepine Agonist-like Discriminative Stimulus Effects in Normal or Diazepam-dependent Rhesus Monkeys [Abstract], Sleep, 2005,28 (Suppl): A45 France, C, et al, Lack of Primary Physical Dependence Effects of Ramelteon in Rhesus Monkeys [Abstract], Sleep, 2005, 28 (Suppl): A45

94. Agomelatine[penultimate slide] Novel antidepressant – melatonergic agonist at MT1 & MT2 receptors, and an antagonist the 5-HT2c receptor – resets desynchronized circadian rhythms Neutral regarding sexual function, sleep, and body weight – equivalent to placebo re: side effects, except for mild dizziness occurring early and which fades over time

95. THE END Good Night Sleep Tight Don’t Let The Bed Bugs Bite