Disorders of sleep and wakefulness
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Disorders of sleep and wakefulness

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    Disorders of sleep and wakefulness Disorders of sleep and wakefulness Presentation Transcript

    • Neurobiology of sleep and wakefulness Insomnia and hypnotics Excessive daytime sleepiness
    • “Sleep and His Half-Brother Death" byJohn William Waterhouse
    • Current pattern of sleep and wakefulness consists of: 16 hours of wakefulness 8 hours of continuous sleepThis sleep/wakefulness pattern :-Unnatural-Recent in human history (since the industrial revolution/electricity).From ancient times until approximately 150-200 years ago: 3-4 hours wakefulness 1-2 hoursSiesta 3-4 hours of wakefulness 1-3 hours evening wakefulness 3-4 hours of first sleep 2-3 hours of wakefulness during the night 3-4 hours of second sleepThe Tiv tribe in Nigeria employ the terms "first sleep" and "second sleep" torefer to specific periods of the night.A. Roger Ekirch; At Day’s Close- Night in Times Past; W. W. Norton & Company, 2005
    • A study by Dr Thomas Wehr at the National Institute of Mental Health:demonstrated that volonteersdeprived of artificial lighting for several weeks went back to thebimodal sleep pattern.The typical subject evolved the following pattern:-lying awake in bed for an hour or two,-then four hours sleep,-then 2-3 hours of “non-anxious wakefulness”-a second sleep-waking for the day’s activities.
    • "And at the wakening of your first sleepeYou shall have a hott drinke made,And at the wakening of your next sleepeYour sorrowes will have a slake.“
    •  So the next time you wake up in the middle of the night, think of your pre-industrial ancestors and relax. Lying awake could be good for you.
    •  Mankind has developed in an environment that is exposed to the rotation of the earth around its own axis, which results in daily rhythmic changes in light intensity.
    •  Organisms responded by evolving cellular clock mechanisms sensitive to light, and by organizing their activities into circadian cycles.
    •  Chronobiology is the science of the biological clocks developed by Franz Halberg. It studies organisms that present with oscillators and organize their activities into 24-hour cycles, such as sleep and wakefulness.
    • What Keeps Us Awake?Histamine keeps thebrain awake.HISTAMINE IS PRODUCED IN THE TMN.Histamine promotes the CALMwakefulness that helps problemsolving, creativity and cognition(unlike the monoamines).
    •  TMN of hypothalamus contains histamine producing neurons that are activated by glutamate and inhibited by GABA. These neurons make up the wakefulness promoter. *Lateral hypothalamus contains orexin neurons that promote weight loss in addition to wakefulness.
    •  VLPO nucleus contains GABA neurons that inhibit TMN and thus promote sleep.
    • TMN SCN VLPOWAKE PROMOTER: CENTRAL CLOCK: SLEEPTuberomammillary Suprachiasmatic PROMOTER:nucleus –TMN-of the nucleus of the Ventrolateralhypothalamus promotes hypothalamus is the preoptic area –wakefulness (produces switch from VLPO-of thehistamine) wakefulness to sleep. hypothalamus promotes sleep Light – ON (produces GABA) Melatonin - OFF
    • Aside from the CentralClock, there arePeripheral clocks in varioustissues
    • Exogenous Cues (Zeitgebers) Endogenous Cues (clock-light, controlling genes)-temperature, -Bmal-social interactions, -Clock-pharmacological -Cryptochrome (Cry)manipulation, -exercise, -Period (Per)-eating/drinking patterns -Rev-ErbA (REV-ERB)
    • POSITIVE REGULATORSCLOCK and BMAL1aretranscriptionfactors, (live in thenucleus).NEGATIVE REGULATORS(live in the cytoplasm):-cryptochrome genefamily (CRY1 and CRY2)-period gene family(PER1, PER2, and PER3).Other CCG:RORREV-ERB,
    • Bmal Bipolar disorderClock Bipolar d/o, schizophrenia, depressionCry DepressionPer Bipolar, Depression, SchizophreniaREV-ERB Bipolar d/o
    • -4-6 sleep cyclesper night-Stage 4, deepsleep, is longerearly in the sleepperiod.-Stage 5, REM,increases infrequency andlength later duringthe sleep period.- Stage 5, REM is20-35% of sleep inadults.
    • Vandekerckhove, M., & Cluydts, R. (2010). Sleep Medicine Reviews, 14(4), 219-226.
    •  The more primitive brain structures including the thalamus and parts of the limbic system become functional first. This suggests that a foundational primitive conscious state must be restored before higher order conscious activity can occur.
    • Know that you do not know! A lot is known about sleep, its pathophysiology, and treatment, yet what we know scientifically about the dream state is far less than what we thought we knew a generation ago. The evidence is overwhelming that REM sleep occurs without dreaming and dreaming without REM sleep. Evidence remains equivocal as to whether any special relationship exists between REM sleep and dreaming.
    • NREM SEIZURES:Nocturnal Frontal Lobe EpilepsyNocturnal Paroxysmal DystoniaEpisodic Nocturnal Wanderings
    • NREM Slow Wave Sleep REM Behavior DisorderTime Early (first 2 hours of sleep) Late (last few hours of sleep)Memory of event No YesArousability Difficult EasyPostevent confusion Yes NoAge Children/Young adults ElderlyGenetic predisposition Likely UnlikelyComorbidities Usually none Neurodegenerative disordersTreatment Conservative BenzodiazepinesBehaviors More complicated, eyes Simple, eyes closed open
    • Polysomnography -four channels of EEG -right and left (EOG), -chin and limb (EMG), -EKG, -environmental noise recording (mean noise).EEG represents stage 1 sleep with an arousal caused by a burstof ambient noise measuring 69 dB(A).
    • Phase delayed circadian rhythm:-common in adolescents anddepressed patients (causes themto fall asleep late).Phase advanced circadian rhythm:-common for elderly individuals(causes them to wake up early inthe morning). Phase Delay: *morning light *evening melatonin Phase Advance: *evening light *morning melatonin
    •  The Morningness-Eveningness Questionnaire (MEQ) is a self- assessment questionnaire. Its main purpose is to measure whether a persons peak sleepiness and alertness is in the morning versus evening. The MEQ consists of 19 multiple-choice questions, with each question having four response options.
    • Aim to reset the Central Clock.Can be used as monotherapy or in combination with medications. The most common aproaches: Sleep phase advance/delay therapy Wake Therapy Bright light therapy Sleep deprivation
    •  Light therapy as adjuvant to SSRIs(major depression) or lithium (bipolar disorder) Light therapy for SAD and non-seasonal depression Total sleep deprivation (Wake Therapy) Partial sleep deprivation in the second half of the night Phase advance of the sleep cycle Dark or rest therapy to stop rapid cycling Dark therapy for mania
    •  Exposure to light alters circadian rhythms and suppresses melatonin release 10,000 lux (bright light) for 30 min/day Useful as a non-pharmacological intervention for depression during pregnancy
    • TIK-301 Melatonin receptor agonist Also has serotonin 5HT 2b and 5HT 2c antagonism Recently finished Phase II clinical trialsNeu-P11 Melatonin agonist Also has affinity for: -serotonin 5-HT 1a, 5-HT 1b, 5-HT 2b Quera Salva MA et al. Current Pharm Des 2011;17(15):1459-70
    • Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    • Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    • Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    • Five benzodiazepines are FDA approved for insomnia :  Flurazepam and Quazepam, (ultra-long half-lives);  Triazolam (ultra-short half-life)  Estazolam and Temazepam (moderate half-lives).Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    •  Benzodiazepines bind to 4 of the 6 different types of GABA-A alpha subunits: alpha 1, alpha 2, alpha 3 and alpha 5. Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    • GABA A receptors containing GABA A receptors containingalpha 1 subunits are involved in alpha 2 or alpha 3 subunitsSleep. are involved in anxiety.
    •  The hypnotics Zaleplon and Zolpidem bind selectively to GABA-A receptors that contain the alpha 1 subunit (sleep). This subunit is important for sleep and possibly for anticonvulsant and amnesic actions. Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    •  The rule of 150 applies. Less than 150 mg –H1 blockade More than 150 mg: SRI, NRI, H1, Alpha 2 and M1 blockade. Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    •  At low doses (1-6 mg/day), doxepin is selective for histamine 1 receptors and thus may be used as a hypnotic. Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    •  Diphenhydramine is a histamine 1 receptor antagonist commonly used as a hypnotic. Diphenhydramine is also a muscarinic 1 receptor antagonist and thus causes anticholinergic effects(blurred vision, constipation, memory problems, dry mouth, etc.)Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press
    • Most psychiatrists disregard Ramelteon, but it deserves a second look. Remelteon is a melatonin 1 and 2 agonist and provides sleep onset, but not sleep maintenance (because of short half life). A preliminary study suggests that Ramelteon has antidepressant effects. NEUROPROTECTION: Because Ramelteon has greater potency and affinity at melatonin receptors, it is suggested that it shares melatonin’s neuroprotective effects.In almost all studies, Ramelteon, in various doses of 4, 8, or 16mg, significantly reduced sleep latency and increased sleep duration.
    •  Excessive Daytime Sleepiness (EDS): The inability to remain fully alert or awake during the wakefulness portion of the sleep/wake cycle.
    •  The precise mechanism of action of modafinil is yet to be fully elucidated. It is known to bind to the dopamine transporter (DAT). Modafinil has low affinity for the DAT. It is possible that the increase in synaptic dopamine leads to increased tonic firing and downstream effects on neurotransmitters involved in wakefulness, such as histamine and orexin/hypocretin.Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 3rd Ed.2008;Cambridge University Press